Review of the neurological benefits of phytocannabinoids.

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“Numerous physical, psychological, and emotional benefits have been attributed to marijuana since its first reported use in 2,600 BC in a Chinese pharmacopoeia. The phytocannabinoids, cannabidiol (CBD), and delta-9-tetrahydrocannabinol (Δ9-THC) are the most studied extracts from cannabis sativa subspecies hemp and marijuana. CBD and Δ9-THC interact uniquely with the endocannabinoid system (ECS). Through direct and indirect actions, intrinsic endocannabinoids and plant-based phytocannabinoids modulate and influence a variety of physiological systems influenced by the ECS.

METHODS:

In 1980, Cunha et al. reported anticonvulsant benefits in 7/8 subjects with medically uncontrolled epilepsy using marijuana extracts in a phase I clinical trial. Since then neurological applications have been the major focus of renewed research using medical marijuana and phytocannabinoid extracts.

RESULTS:

Recent neurological uses include adjunctive treatment for malignant brain tumors, Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, neuropathic pain, and the childhood seizure disorders Lennox-Gastaut and Dravet syndromes. In addition, psychiatric and mood disorders, such as schizophrenia, anxiety, depression, addiction, postconcussion syndrome, and posttraumatic stress disorders are being studied using phytocannabinoids.

CONCLUSIONS:

In this review we will provide animal and human research data on the current clinical neurological uses for CBD individually and in combination with Δ9-THC. We will emphasize the neuroprotective, antiinflammatory, and immunomodulatory benefits of phytocannabinoids and their applications in various clinical syndromes.”

https://www.ncbi.nlm.nih.gov/pubmed/29770251

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5938896/

Effect of Cannabidiol on Drop Seizures in the Lennox-Gastaut Syndrome.

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“Cannabidiol has been used for treatment-resistant seizures in patients with severe early-onset epilepsy.

We investigated the efficacy and safety of cannabidiol added to a regimen of conventional antiepileptic medication to treat drop seizures in patients with the Lennox-Gastaut syndrome, a severe developmental epileptic encephalopathy.

Among children and adults with the Lennox-Gastaut syndrome, the addition of cannabidiol at a dose of 10 mg or 20 mg per kilogram per day to a conventional antiepileptic regimen resulted in greater reductions in the frequency of drop seizures than placebo.”

https://www.ncbi.nlm.nih.gov/pubmed/29768152

https://www.nejm.org/doi/10.1056/NEJMoa1714631

Control of excessive neural circuit excitability and prevention of epileptic seizures by endocannabinoid signaling

Cellular and Molecular Life Sciences

“Progress in research on endocannabinoid signaling has greatly advanced our understanding of how it controls neural circuit excitability in health and disease.

In general, endocannabinoid signaling at excitatory synapses suppresses seizures by inhibiting glutamate release. In contrast, endocannabinoid signaling promotes seizures by inhibiting GABA release at inhibitory synapses. The physiological distribution of endocannabinoid signaling molecules becomes disrupted with the development of epileptic focus in patients with mesial temporal lobe epilepsy and in animal models of experimentally induced epilepsy.

Augmentation of endocannabinoid signaling can promote the development of epileptic focus at initial stages. However, at later stages, increased endocannabinoid signaling delays it and suppresses spontaneous seizures. Thus, the regulation of endocannabinoid signaling at specific synapses that cause hyperexcitability during particular stages of disease development may be effective for treating epilepsy and epileptogenesis.”

https://link.springer.com/article/10.1007/s00018-018-2834-8

http://www.x-mol.com/paper/661834

Efficacy of CBD-enriched medical cannabis for treatment of refractory epilepsy in children and adolescents – An observational, longitudinal study.

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“The objective of this observational study was to evaluate the efficacy of medical cannabis for the treatment of refractory epilepsy.

Fifty-seven patients (age 1-20 years) with epilepsy of various etiologies were treated with Cannabis oil extract (CBD/THC ratio of 20:1) for at least 3 months (Median follow up time-18 months). Forty-Six Patients were included in the efficacy analysis. Average CBD dose was11.4 mg/kg/d.

Twenty-six patients (56%) had ≤50% reduction in mean monthly seizure frequency. There was no statistically significant difference in response rate among various epilepsy etiologies, and cannabis strain used.

Younger age at treatment onset (<10 years) and higher CBD dose (>11 mg/kg/d) were associated with better response to treatment. Adverse reactions were reported in 46% of patients and were the main reason for treatment cessation.

Our results suggest that adding CBD-enriched cannabis extract to the treatment regimen of patients with refractory epilepsy may result in a significant reduction in seizure frequency according to parental reports.”

Antiepileptogenic Effect of Subchronic Palmitoylethanolamide Treatment in a Mouse Model of Acute Epilepsy.

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“Research on the antiepileptic effects of (endo-)cannabinoids has remarkably progressed in the years following the discovery of fundamental role of the endocannabinoid (eCB) system in controlling neural excitability. Moreover, an increasing number of well-documented cases of epilepsy patients exhibiting multi-drug resistance report beneficial effects of cannabis use.

Pre-clinical and clinical research has increasingly focused on the antiepileptic effectiveness of exogenous administration of cannabinoids and/or pharmacologically induced increase of eCBs such as anandamide (also known as arachidonoylethanolamide [AEA]). Concomitant research has uncovered the contribution of neuroinflammatory processes and peripheral immunity to the onset and progression of epilepsy.

Accordingly, modulation of inflammatory pathways such as cyclooxygenase-2 (COX-2) was pursued as alternative therapeutic strategy for epilepsy. Palmitoylethanolamide (PEA) is an endogenous fatty acid amide related to the centrally and peripherally present eCB AEA, and is a naturally occurring nutrient that has long been recognized for its analgesic and anti-inflammatory properties.

Neuroprotective and anti-hyperalgesic properties of PEA were evidenced in neurodegenerative diseases, and antiepileptic effects in pentylenetetrazol (PTZ), maximal electroshock (MES) and amygdaloid kindling models of epileptic seizures. Moreover, numerous clinical trials in chronic pain revealed that PEA treatment is devoid of addiction potential, dose limiting side effects and psychoactive effects, rendering PEA an appealing candidate as antiepileptic compound or adjuvant.

In the present study, we aimed at assessing antiepileptic properties of PEA in a mouse model of acute epileptic seizures induced by systemic administration of kainic acid (KA).

Here, we demonstrate that subchronic administration of PEA significantly alleviates seizure intensity, promotes neuroprotection and induces modulation of the plasma and hippocampal eCB and eiC levels in systemic KA-injected mice.”

https://www.ncbi.nlm.nih.gov/pubmed/29593494

https://www.frontiersin.org/articles/10.3389/fnmol.2018.00067/full

Cannabis in epilepsy: From clinical practice to basic research focusing on the possible role of cannabidivarin.

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“Cannabidivarin (CBDV) and cannabidiol (CBD) have recently emerged among cannabinoids for their potential antiepileptic properties, as shown in several animal models.

We report the case of a patient affected by symptomatic partial epilepsy who used cannabis as self-medication after the failure of countless pharmacological/surgical treatments.

After cannabis administration, a dramatic clinical improvement, in terms of both decrease in seizure frequency and recovery of cognitive functions, was observed, which might parallel high CBDV plasma concentrations.

Our patient’s electroclinical improvement supports the hypothesis that cannabis could actually represent an effective, well-tolerated antiepileptic drug.

Moreover, the experimental data suggest that CBDV may greatly contribute to cannabis anticonvulsant effect through its possible GABAergic action.”

https://www.ncbi.nlm.nih.gov/pubmed/29588939

https://onlinelibrary.wiley.com/doi/abs/10.1002/epi4.12015

Cannabidiol exerts antiepileptic effects by restoring hippocampal interneuron functions in a temporal lobe epilepsy model.

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“A non-psychoactive phytocannabinoid, cannabidiol (CBD), shows promising results as an effective potential antiepileptic drug in some forms of refractory epilepsy.

In an attempt to understand the mechanisms by which CBD exerts its anti-seizure effects, we investigated the effects of CBD at synaptic connections, and the intrinsic membrane properties of hippocampal CA1 pyramidal cells and two major inhibitory interneurons: fast spiking, parvalbumin -expressing (PV) and adapting, cholecystokinin-expressing (CCK) interneurons.

CONCLUSIONS & IMPLICATIONS:

In conclusion, our data suggest CBD restores excitability and morphological impairment in epileptic models to pre-epilepsy control levels through multiple mechanisms to restore normal network function.”

https://www.ncbi.nlm.nih.gov/pubmed/29574880

https://bpspubs.onlinelibrary.wiley.com/doi/abs/10.1111/bph.14202

Anticonvulsive effects of endocannabinoids; an investigation to determine the role of regulatory components of endocannabinoid metabolism in the Pentylenetetrazol induced tonic- clonic seizures.

Metabolic Brain Disease

“2-Arachidonoylglycerol (2-AG) and anandamide are two major endocannabinoids produced, released and eliminated by metabolic pathways.

Anticonvulsive effect of 2-AG and CB1 receptor is well-established. Herein, we designed to investigate the anticonvulsive influence of key components of the 2-AG and anandamide metabolism.

It seems extracellular accumulation of 2-AG or anandamide has anticonvulsive effect through the CB1 receptor, while intracellular anandamide accumulation is proconvulsive through TRPV1.”

https://www.ncbi.nlm.nih.gov/pubmed/29504066

https://link.springer.com/article/10.1007%2Fs11011-018-0195-5

Cannabidiol for treatment of refractory childhood epilepsies: Experience from a single tertiary epilepsy center in Slovenia.

“Refractory epilepsies in children present a major burden for patients and their families. Cannabidiol (CBD) has been suggested as a potential treatment for refractory epilepsies. The aim of this study was to evaluate the effectiveness of add-on therapy with CBD for the treatment of refractory childhood epilepsies.

METHOD:

Patients with childhood-onset refractory epilepsy, treated at the tertiary epilepsy center of the University Children’s Hospital Ljubljana, Slovenia, were included in the study. Add-on therapy with CBD was initiated once the child’s epilepsy was categorized as pharmacoresistant to other antiepileptic drugs/therapies. The dosage of CBD was gradually increased to at least 8mg/kg/day. The effect of CBD treatment was evaluated by the reduction in seizure burden and presence of side effects (positive and negative). Serial electroencephalography was performed in some children.

RESULTS:

Sixty-six patients were included in the analysis. Thirty-two (48.5%) patients had a more than 50% improvement regarding seizure burden, 14 of whom (21.2%) became seizure-free. None of the patients reported worsening of seizure frequency, but CBD had no effect in 15 (22.7%) patients. Some patients reported less vigorous seizures, shorter duration of seizures, shorter time to recovery, and other positive side effects of CBD treatment. Adverse effects were reported in 5/66 children.

CONCLUSIONS:

In our cohort of patients, CBD was found to have potential benefits as add-on therapy for refractory childhood epilepsies, mainly by reducing seizure burden.”

https://www.ncbi.nlm.nih.gov/pubmed/29526578

http://www.epilepsybehavior.com/article/S1525-5050(17)30942-3/fulltext

Evidence for cannabis and cannabinoids for epilepsy: a systematic review of controlled and observational evidence.

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“Review evidence for cannabinoids as adjunctive treatments for treatment-resistant epilepsy.

Systematic search of Medline, Embase and PsycINFO was conducted in October 2017. Outcomes were: 50%+ seizure reduction, complete seizure freedom; improved quality of life (QoL).

Tolerability/safety were assessed by study withdrawals, adverse events (AEs) and serious adverse events (SAEs). Analyses were conducted in Stata V.15.0. 36 studies were identified: 6 randomised controlled trials (RCTs), 30 observational studies. Mean age of participants was 16.1 years (range 0.5-55 years).

Cannabidiol (CBD) 20 mg/kg/day was more effective than placebo at reducing seizure frequency by 50%+(relative risk (RR) 1.74, 95% CI 1.24 to 2.43, 2 RCTs, 291 patients, low Grades of Recommendation, Assessment, Development and Evaluation (GRADE) rating). The number needed to treat for one person using CBD to experience 50%+ seizure reduction was 8 (95% CI 6 to 17).

CBD was more effective than placebo at achieving complete seizure freedom (RR 6.17, 95% CI 1.50 to 25.32, 3 RCTs, 306 patients, low GRADE rating), and improving QoL (RR 1.73, 95% CI 1.33 to 2.26), however increased risk of AEs (RR 1.24, 95% CI 1.13 to 1.36) and SAEs (RR 2.55, 95% CI 1.48 to 4.38). Pooled across 17 observational studies, 48.5% (95% CI 39.0% to 58.1%) of patients reported 50%+ reductions in seizures; in 14 observational studies 8.5% (95% CI 3.8% to 14.5%) were seizure-free. Twelve observational studies reported improved QoL (55.8%, 95% CI 40.5 to 70.6); 50.6% (95% CI 31.7 to 69.4) AEs and 2.2% (95% CI 0 to 7.9) SAEs.

Pharmaceutical-grade CBD as adjuvant treatment in paediatric-onset drug-resistant epilepsy may reduce seizure frequency. Existing RCT evidence is mostly in paediatric samples with rare and severe epilepsy syndromes; RCTs examining other syndromes and cannabinoids are needed.”

https://www.ncbi.nlm.nih.gov/pubmed/29511052

http://jnnp.bmj.com/content/early/2018/02/05/jnnp-2017-317168

“Cannabis Compounds Reduce Epileptic Seizure Frequency In Children And Teenagers” http://www.iflscience.com/health-and-medicine/cannabis-compounds-reduce-epileptic-seizure-frequency-in-children-and-teenagers/

“Cannabis ingredient ‘reduces epilepsy seizures'”  https://www.webmd.boots.com/news/20180307/cannabis-ingredient-for-epilepsy-seizures

“Marijuana Derivative Successfully Treats Teen Epilepsy in New Experiments”  https://www.inverse.com/article/41985-cbd-marijuana-treat-seizures-epilepsy