Therapeutic applicability of cannabidiol and other phytocannabinoids in epilepsy, multiple sclerosis and Parkinson’s disease and in comorbidity with psychiatric disorders

pubmed logo

“Studies have demonstrated the neuroprotective effect of cannabidiol (CBD) and other Cannabis sativa L. derivatives on diseases of the central nervous system caused by their direct or indirect interaction with endocannabinoid system-related receptors and other molecular targets, such as the 5-HT1A receptor, which is a potential pharmacological target of CBD. Interestingly, CBD binding with the 5-HT1A receptor may be suitable for the treatment of epilepsies, parkinsonian syndromes and amyotrophic lateral sclerosis, in which the 5-HT1A serotonergic receptor plays a key role. The aim of this review was to provide an overview of cannabinoid effects on neurological disorders, such as epilepsy, multiple sclerosis and Parkinson’s diseases, and discuss their possible mechanism of action, highlighting interactions with molecular targets and the potential neuroprotective effects of phytocannabinoids. CBD has been shown to have significant therapeutic effects on epilepsy and Parkinson’s disease, while nabiximols contribute to a reduction in spasticity and are a frequent option for the treatment of multiple sclerosis. Although there are multiple theories on the therapeutic potential of cannabinoids for neurological disorders, substantially greater progress in the search for strong scientific evidence of their pharmacological effectiveness is needed.”

https://pubmed.ncbi.nlm.nih.gov/38477419/

https://onlinelibrary.wiley.com/doi/10.1111/bcpt.13997

Purified cannabidiol as add-on therapy in children with treatment-resistant infantile epileptic spasms syndrome

pubmed logo

“Objective: The aim of this study was to assess efficacy, safety, and tolerability of highly purified cannabidiol oil (CBD) as add-on therapy for the treatment of a series of patients with infantile epileptic spasms syndrome (IESS) who were resistant to antiseizure medications and ketogenic dietary therapy.

Material and methods: We conducted a retrospective analysis of the medical records of 28 infants with treatment-resistant IESS aged 6 to 21 months who received highly purified CBD between July 2021 and June 2023. Data were collected on neurological examinations, EEG, Video-EEG and polygraphic recordings, imaging studies, laboratory testing, and seizure frequency, type, and duration, and adverse effects. As the primary outcome, a reduction of frequency of epileptic spasms (ES) was assessed. ES freedom was considered after a minimal time of 1 month without ES.

Results: Sixteen male and 12 female patients, aged 6-21 months, who received CBD for treatment-resistant IESS were included. The etiology was structural in 10, Down syndrome in seven, genetic in nine, and unknown in two. Initial CBD dose was 2 mg/kg/day, which was uptitrated to a median dose of 25 mg/kg/day (range, 2-50). Prior to CBD initiation, patients had a median of 69 ES in clusters per day (range, 41-75) and of 10 focal seizures per week (range, 7-13). After a mean and median follow-up of 15 and 12.5 months (range, 6-26 months), seven patients were ES free and 12 had a >50 % ES reduction. Five of seven patients (71 %) with Down syndrome and 3/5 (60 %) with cerebral palsy responded well. Adverse effects were mild. EEG improvements correlated with ES reductions.

Conclusion: In this study evaluating the use of CBD in children with IESS, 19/28 (67.8 %) had a more than 50 % ES reduction with good tolerability.”

https://pubmed.ncbi.nlm.nih.gov/38237316/

https://www.seizure-journal.com/article/S1059-1311(24)00018-9/fulltext

Caregiver-reported outcomes with real-world use of cannabidiol in Lennox-Gastaut syndrome and Dravet syndrome from the BECOME survey

pubmed logo

“Purpose: Plant-derived highly purified cannabidiol (CBD) reduced the frequency of seizures associated with Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS) and improved the overall condition of patients in placebo-controlled phase 3 clinical trials. Anecdotal reports also suggest a positive effect on nonseizure outcomes. In this study, we aimed to identify, through a caregiver survey which nonseizure outcomes were most likely to change in these patients.

Methods: The BEhavior, COgnition, and More with Epidiolex® (BECOME) was a 20-minute, cross-sectional, online survey that was developed with extensive input from caregivers, healthcare professionals, and epilepsy researchers, and was based on questions from validated measures and previously published caregiver reports. US-based caregivers (from Jazz Pharmaceuticals patient/caregiver database) of people with LGS or DS who were treated with CBD (Epidiolex®, 100 mg/mL oral solution) for ≥3 months were asked to compare the past month to the period before CBD initiation and rate their impression of changes using symmetrical Likert scales

Results: A total of 498 caregivers (97% parents) of patients with LGS (80%) or DS (20%) completed the survey. Mean (range) age of patients was 16 (1-73) years, and 52% were male. Patients were taking a median CBD dose of 14 mg/kg/d and median 4 concomitant antiseizure medications. A large proportion of respondents reported improvements in ≥1 survey question for all nonseizure-related domains: alertness, cognition, and executive function (85%); emotional functioning (82%); language and communication (79% in nonverbal patients and 74% in verbal); activities of daily living (51%); sleep (51%); and physical functioning (46%). Respondents reported improvements in seizure-related domains, including overall seizure frequency (85%), overall seizure severity (76%), seizure-free days per week for ≥1 seizure type (67%), and seizure freedom during the past month (16%). The majority of respondents who reported reduction in seizure frequency also reported improvements in nonseizure outcomes domains (51-80%). However, improvements in nonseizure outcomes (18-56%) were also reported in patients who either had no change or worsening of seizure frequency.

Conclusions: This survey characterized and quantified caregiver impression of changes in the seizure and nonseizure outcomes in patients taking add-on CBD treatment. Overall, 93% of caregivers reported planning to continue CBD treatment, primarily because of reduced seizure burden but also because of improvements in nonseizure-related outcomes. Despite the limitations that are associated with a retrospective survey-based study design, these results support further evaluation of the effect of CBD treatment on nonseizure outcomes among patients with LGS or DS.”

https://pubmed.ncbi.nlm.nih.gov/38183688/

https://www.sciencedirect.com/science/article/pii/S092012112300205X?via%3Dihub

Real-Life Experience With Purified Cannabidiol Treatment for Refractory Epilepsy: A Multicenter Retrospective Study

pubmed logo

“Background: Drug-resistant epilepsy (DRE) affects the development and quality of life of children and young adults. We analyzed the effectiveness and safety of purified CBD in this population.

Methods: A retrospective analysis of medical records of 139 children and young adults (54.7% female, median age 12.0 years) with DRE treated with purified CBD from 2018 to 2022 at five medical centers in Israel.

Results: The most common diagnosis was Lennox-Gastaut syndrome (37.4%) followed by Dravet syndrome (16.5%) and tuberous sclerosis complex (16.5%). Median purified CBD dose was 12.5 mg/kg (range 2.5 to 20.0), and median treatment duration was 9.0 months (range 0.5 to 48.0). Most patients (92.2%) had a reduced seizure frequency following treatment initiation; 41.1% had >50% reduction. Fifty-three patients (38.1%) had positive effects: improved alertness (31.7%), improved speech (10.1%), and achievement of new developmental milestones (2.2%). A multivariate linear model assessing predictive factors for seizure reduction demonstrated that patients previously treated with CBD oils, especially those with >50% seizure reduction on prior treatment, were also more likely to have a reduced seizure frequency while they were treated with purified CBD (P = 0.01, P < 0.0001). Development, diagnosis, age, purified CBD dose (0 to 10 mg/kg/day vs 10 to 20 mg/kg/day), and concomitant treatment with clobazam, valproic acid, or everolimus did not affect seizure reduction by purified CBD. The most common adverse events were irritability (20.9%) and drowsiness (12.9%).

Conclusion: Purified CBD is well-tolerated and effective in reducing seizure frequency in children and young adults with DRE.”

https://pubmed.ncbi.nlm.nih.gov/37995414/

https://www.pedneur.com/article/S0887-8994(23)00362-4/fulltext

Cannabidiol Anticonvulsant Effects Against Lithium-Pilocarpine-Induced Status Epilepticus in Male Rats Are Mediated by Neuroinflammation Modulation and Cannabinoids 1 (CB1), But Not CB2 and GABAA Receptors

pubmed logo

“Background: Status epilepticus (SE) is a series of seizures that can lead to serious neurological damages. Cannabidiol (CBD) is extracted from the cannabis plant, which has been approved as an antiseizure medication. This study aimed to determine the efficacy of various doses of CBD on lithium-pilocarpine-induced SE in rats and possible involvement of multiple pharmacological pathways. We hypothesized that cannabinoid receptors type 1 (CB1) and CB2, as well as GABAA receptors, might have important roles in the anticonvulsant effects of CBD against SE by its anti-inflammatory effects. 

Methods: SE was induced by intraperitoneal (i.p.) injection of lithium (127 mg/kg, i.p.) and pilocarpine (60 mg/kg, i.p., 20 h after lithium). Forty-two male rats were divided into seven groups (including control and sham groups), and the treated groups received different doses of CBD (1, 3, 5, 10, and 25 mg/kg, i.p.). SE score was recorded over the next 2 h following pilocarpine injection. Then, we measured the levels of pro-inflammatory cytokines, including interleukin (IL)-lβ and tumor necrosis factor (TNF)-α, using ELISA kits. Also we analyzed the expression of CB1, CB2, and GABAA receptors using the Western blot technique. 

Results: CBD at 5 mg/kg significantly reduced Racine’s scale and duration of seizures, and increased the onset time of seizure. Moreover, CBD 5 mg/kg caused significant reductions in the elevated levels of IL-lβ and TNF-α, as well as a significant increase in the decreased level of CB1 receptor expression compared to the control group. In other word, CBD reverted the effects of SE in terms of neuroinflammation and CB1 receptor. Based on the obtained results, CBD was not able to restore the declined levels of CB2 or GABAA receptors. 

Conclusion: Our study found anticonvulsant effects of CBD on the SE rat model induced by lithium-pilocarpine with probable involvement of CB1 receptors and anti-inflammatory effects by reducing IL-1β and TNF-α markers independent of CB2 and GABAA receptors.”

https://pubmed.ncbi.nlm.nih.gov/37976207/

https://www.liebertpub.com/doi/10.1089/can.2023.0067

Cannabinoid treatments in epilepsy and seizure disorders

pubmed logo

“Cannabis was used to treat convulsions and other disorders since ancient times. In the last few decades, preclinical animal studies and clinical investigations have established the role of cannabidiol (CBD) in treating epilepsy and seizures and support potential therapeutic benefits for cannabinoids in other neurological and psychiatric disorders. Here, we comprehensively review the role of cannabinoids in epilepsy. We briefly review the diverse physiological processes mediating the central nervous system response to cannabinoids, including D9-THC, cannabidiol, and terpenes. Next, we characterize the anti- and proconvulsive effects of cannabinoids from animal studies of acute seizures and chronic epileptogenesis. We then review the clinical literature on using cannabinoids to treat epilepsy, including anecdotal evidence and case studies as well as the more recent randomized-controlled clinical trials that led to FDA approval of CBD for some types of epilepsy. Overall, we seek to evaluate our current understanding of cannabinoids in epilepsy and focus future research on unanswered questions.”

https://pubmed.ncbi.nlm.nih.gov/37882730/

https://journals.physiology.org/doi/abs/10.1152/physrev.00049.2021

Cannabinoids and endocannabinoids as therapeutics for nervous system disorders: preclinical models and clinical studies

pubmed logo

“Cannabinoids are lipophilic substances derived from Cannabis sativa that can exert a variety of effects in the human body. They have been studied in cellular and animal models as well as in human clinical trials for their therapeutic benefits in several human diseases.

Some of these include central nervous system (CNS) diseases and dysfunctions such as forms of epilepsy, multiple sclerosis, Parkinson’s disease, pain and neuropsychiatric disorders. In addition, the endogenously produced cannabinoid lipids, endocannabinoids, are critical for normal CNS function, and if controlled or modified, may represent an additional therapeutic avenue for CNS diseases. This review discusses in vitro cellular, ex vivo tissue and in vivo animal model studies on cannabinoids and their utility as therapeutics in multiple CNS pathologies. In addition, the review provides an overview on the use of cannabinoids in human clinical trials for a variety of CNS diseases.

Cannabinoids and endocannabinoids hold promise for use as disease modifiers and therapeutic agents for the prevention or treatment of neurodegenerative diseases and neurological disorders.”

https://pubmed.ncbi.nlm.nih.gov/37843213/

https://journals.lww.com/nrronline/fulltext/2024/04000/cannabinoids_and_endocannabinoids_as_therapeutics.22.aspx

Phytocannabinoids Reduce Seizures in Larval Zebrafish and Affect Endocannabinoid Gene Expression

pubmed logo

“Cannabis has demonstrated anticonvulsant properties, and about thirty percent of epileptic patients do not have satisfactory seizure management with standard treatment and could potentially benefit from cannabis-based intervention. Here, we report the use of cannabinoids to treat pentylenetetrazol (PTZ)-induced convulsions in a zebrafish model, their effect on gene expression, and a simple assay for assessing their uptake in zebrafish tissues. Using an optimized behavioral assay, we show that cannabidiol (CBD) and cannabichromene (CBC) and cannabinol (CBN) are effective at reducing seizures at low doses, with little evidence of sedation, and our novel HPLC assay indicates that CBC is effective with the lowest accumulation in larval tissues. All cannabinoids tested were effective at higher concentrations. Pharmacological manipulation of potential receptors demonstrates that Gpr55 partially mediates the anticonvulsant effects of CBD. Treatment of zebrafish larvae with endocannabinoids, such as 2-arachidonoylglycerol (2-AG) and anandamide (AEA), altered larvae movement, and the expression of genes that regulate their metabolism was affected by phytocannabinoid treatment, highlighting the possibility that changes to endocannabinoid levels may represent one facet of the anticonvulsant effect of phytocannabinoids.”

https://pubmed.ncbi.nlm.nih.gov/37759798/

https://www.mdpi.com/2218-273X/13/9/1398

Highly purified cannabidiol in the treatment of drug-resistant epilepsies: A real-life impact on seizure frequency, quality of life, behavior, and sleep patterns from a single Italian center

pubmed logo

“Seizure frequency in treatment-resistant epilepsies seems to be decreased by cannabidiol (CBD), but contrasting data are available on its effect on sleep, behavior, and quality of life (QoL), and no data is reported on its effect on parental stress in patients with epilepsy (PWE). Thus, we conducted a retrospective study on a cohort of children and adults with drug-resistant epilepsy (DRE) who had been treated with highly purified, pharmaceutical-grade CBD to evaluate its effects on seizure frequency, QoL, behavior, parental stress, and sleep. Eighteen patients (12 adults and 6 children) were included in the cohort and followed for a median of 9 months. At the last follow-up (Tn), nine patients (50%) were considered CBD responders with at least a 50% decrease in seizure frequency. No serious adverse effects were found. No statistically significant differences were found concerning sleep, including daytime sleepiness, and no statistically significant effect was found on parental stress at Tn. An improvement was found for social interaction in quality of life (p < 0.05) for all patients.

Our results demonstrate that CBD is a safe and effective antiseizure medication (ASM).

CBD doesn’t seem to affect sleep measures in adults and children or worsen daytime sleepiness. However, CBD improves specific QoL measures, which could indicate a possible use of CBD for other childhood disabilities. No impact of CBD was seen on parental stress, which could possibly be due to the limited follow-up or could mean that parental stress is not dependent on seizure frequency.”

https://pubmed.ncbi.nlm.nih.gov/37677907/

“Cannabidiol (CBD) is a safe and effective antiseizure medication (ASM).”

https://www.epilepsybehavior.com/article/S1525-5050(23)00328-1/fulltext

Efficacy and tolerance of cannabidiol in the treatment of epilepsy in patients with Rett syndrome

pubmed logo

“We aim to assess the efficacy and tolerance of cannabidiol as adjunctive therapy for Rett syndrome (RTT) patients with epilepsy. We conducted a longitudinal observational study through a monocentric cohort of 46 patients with RTT. Patients were recruited from March 2020 to October 2022 and were treated with Epidyolex® (cannabidiol, CBD, 100 mg/ml oral solution). In our cohort, 26 patients had associated epilepsy (26/46 (56%)), and 10/26 (38%) were treated with CBD, in combination with clobazam in 50% of cases. The median dose at their last follow-up was 15 mg/kg/d. The median treatment duration was 13 months (range, 1-32 mo.). CBD reduced the incidence of seizures in seven out of ten patients (70%) with one seizure-free patient, two patients with a reduction of seizures of more than 75%, and four patients with a decrease of more than 50%. No aggravation of symptoms or adverse effects were observed. Only one patient experienced a transitory drooling and somnolence episode at the CBD initiation. Half of the patients showed a reduction in agitation and/or anxiety attacks, and an improvement in spasticity was reported in 4/10 (40%) of patients. CBD appears to have potential therapeutic value for the treatment of drug-resistant epilepsy in Rett syndrome. CBD is well tolerated and, when used in combination with clobazam, may increase the effectiveness of clobazam alone.”

https://pubmed.ncbi.nlm.nih.gov/37485779/

https://onlinelibrary.wiley.com/doi/10.1002/epi4.12796