The anticonvulsant effects of cannabidiol in experimental models of epileptic seizures: from behavior and mechanisms to clinical insights.

Neuroscience & Biobehavioral Reviews“Epilepsy is a neurological disorder characterized by the presence of seizures and neuropsychiatric comorbidities. Despite the number of antiepileptic drugs, one-third of patients did not have their seizures under control, leading to pharmacoresistance epilepsy.

Cannabis sativa has been used since ancient times in Medicine for the treatment of many diseases, including convulsive seizures.

In this context, Cannabidiol (CBD), a non-psychoactive phytocannabinoid present in Cannabis, has been a promising compound for treating epilepsies due to its anticonvulsant properties in animal models and humans, especially in pharmacoresistant patients. In this review, we summarize evidence of the CBD anticonvulsant activities present in a great diversity of animal models. Special attention was given to behavioral CBD effects and its translation to human epilepsies.

CBD anticonvulsant effects are associated with a great variety of mechanisms of action such as endocannabinoid and calcium signaling. CBD has shown effectiveness in the clinical scenario for epilepsies, but its effects on epilepsy-related comorbidities are scarce even in basic research. More detailed and complex behavioral evaluation about CBD effects on seizures and epilepsy-related comorbidities are required.”

https://www.ncbi.nlm.nih.gov/pubmed/31954723

“CBD presents anticonvulsant behavioral effects in animal models of epilepsy. CBD induces neuroprotection in animal models of epileptic seizures. Multiple mechanisms of action are associated to CBD anticonvulsant effects. Animal models support CBD therapeutic use for epilepsies treatment.”

https://www.sciencedirect.com/science/article/pii/S014976341931067X?via%3Dihub

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Neuroprotective and Neuromodulatory Effects Induced by Cannabidiol and Cannabigerol in Rat Hypo-E22 cells and Isolated Hypothalamus.

antioxidants-logo “Cannabidiol (CBD) and cannabigerol (CBG) are non-psychotropic terpenophenols isolated from Cannabis sativa, which, besides their anti-inflammatory/antioxidant effects, are able to inhibit, the first, and to stimulate, the second, the appetite although there are no studies elucidating their role in the hypothalamic appetite-regulating network. Consequently, the aim of the present research is to investigate the role of CBD and CBG in regulating hypothalamic neuromodulators. Comparative evaluations between oxidative stress and food intake-modulating mediators were also performed.

RESULTS:

Both CBD and CBG inhibited NPY and POMC gene expression and decreased the 3-HK/KA ratio in the hypothalamus. The same compounds also reduced hypothalamic NE synthesis and DA release, whereas the sole CBD inhibited 5-HT synthesis.

CONCLUSION:

The CBD modulates hypothalamic neuromodulators consistently with its anorexigenic role, whereas the CBG effect on the same mediators suggests alternative mechanisms, possibly involving peripheral pathways.”

https://www.ncbi.nlm.nih.gov/pubmed/31941059

https://www.mdpi.com/2076-3921/9/1/71

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Cannabidiol (CBD) for Treatment of Neurofibromatosis-related Pain and Concomitant Mood Disorder: A Case Report.

Image result for cureus journal“Neurofibromatosis type 1 (NF1) is a common genetic disorder. Pain is a major symptom of this disease which can be secondary to the development of plexiform and subcutaneous neurofibromas, musculoskeletal symptoms (such as scoliosis and pseudoarthrosis), and headaches. Visible neurofibromas add significant psychosocial distress for NF1 patients. Along with the chronic pain, psychosocial distress contributes to associated mood disorders, such as depression and anxiety.

Cannabis has been the focus of many studies for treating multiple conditions, including epilepsy, multiple sclerosis, Parkinsonism disease, and many chronic pain conditions. Cannabidiol (CBD) is the major non-psychotropic component of cannabis. CBD has shown anti-inflammatory and analgesic properties, as well as having mood stabilizer and anxiolytic effects.

In this report, we present the use of cannabidiol (CBD) for the management of chronic pain and concomitant mood disorder in an NF1 patient.”

https://www.ncbi.nlm.nih.gov/pubmed/31938604

https://www.cureus.com/articles/23602-cannabidiol-cbd-for-treatment-of-neurofibromatosis-related-pain-and-concomitant-mood-disorder-a-case-report

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Use of cannabinoids in cancer patients: A Society of Gynecologic Oncology (SGO) clinical practice statement.

Gynecologic Oncology“Tetrahydrocannabinol (THC), cannabidiol (CBD) and cannabinol (CBN) affect the human endocannabinoid system.

Cannabinoids reduce chemotherapy induced nausea or vomiting (CINV) and neuropathic pain.

Each state has its own regulations for medical and recreational cannabis use.

Effects of cannabinoids on chemotherapy, immunotherapy, and tumor growth remain under investigation.

Providers should focus indications, alternatives, risks and benefits of medical cannabis use to make appropriate referrals.”

https://www.ncbi.nlm.nih.gov/pubmed/31932107

https://www.gynecologiconcology-online.net/article/S0090-8258(19)31805-0/fulltext

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The role of cannabinoids in epilepsy treatment: a critical review of efficacy results from clinical trials.

Image result for Epileptic Disorders journal “CBD was shown to have anti-seizure activity based on in vitro and in vivo models.

However, several reports of small series or case reports of the use of cannabis extracts in epilepsy yielded contradictory results and the efficacy of cannabis use in patients with epilepsy have also been inconclusive.

In 2013, the first Phase 1 trial for a purified form of CBD (Epidiolex/Epidyolex; >99% CBD), developed by GW Pharma, showed some efficacy signals and subsequently, a comprehensive program on the efficacy and tolerability of this compound for the treatment of drug-resistant epilepsies was initiated.

Results of these trials led to the FDA and EMA approval respectively in 2018 and 2019 for the treatment of seizures associated with two rare epilepsies: Lennox-Gastaut syndrome (LGS) or Dravet syndrome (DS) in patients two years of age and older.

Thus, CBD became the first FDA-approved purified drug substance derived from cannabis and also the first FDA-approved drug for the treatment of seizures in DS.

We detail the clinical studies using purified CBD (Epidiolex/Epidyolex), including the first open interventional exploratory study and Randomized Control Ttrials for DS and LGS.”

https://www.ncbi.nlm.nih.gov/pubmed/31916540

https://www.jle.com/fr/revues/epd/e-docs/the_role_of_cannabinoids_in_epilepsy_treatment_a_critical_review_of_efficacy_results_from_clinical_trials_316030/article.phtml

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The proposed mechanism of action of CBD in epilepsy.

Image result for Epileptic Disorders journal“Highly purified cannabidiol (CBD) (approved as Epidiolex® in the United States) has demonstrated efficacy with an acceptable safety profile in patients with Lennox-Gastaut or Dravet syndrome in four randomized controlled trials.

While the mechanism of action of CBD underlying the reduction of seizures in humans is unknown, CBD possesses affinity for multiple targets, across a range of target classes, resulting in functional modulation of neuronal excitability, relevant to the pathophysiology of many disease types, including epilepsy.

Here we present the pharmacological data supporting the role of three such targets, namely Transient receptor potential vanilloid-1 (TRPV1), the orphan G protein-coupled receptor-55 (GPR55) and the equilibrative nucleoside transporter 1 (ENT-1).”

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Efficacy and Tolerance of Synthetic Cannabidiol for Treatment of Drug Resistant Epilepsy.

Image result for frontiers in neurology“Controlled and open label trials have demonstrated efficacy of cannabidiol for certain epileptic encephalopathies.

However, plant derived cannabidiol products have been used almost exclusively. Efficacy of synthetically derived cannabidiol has not been studied before.

The objective of this study was to evaluate tolerability and efficacy of synthetic cannabidiol in patients with pharmacoresistant epilepsy.

Efficacy and tolerance in our study of synthetic CBD treatment in pharmacoresistant epilepsy is similar to open label studies using plant derived CBD.

Regarding economic and ecological aspects, synthetic cannabidiol might be a reasonable alternative to plant derived cannabidiol.”

https://www.ncbi.nlm.nih.gov/pubmed/31920934

“Over the last decade, the therapeutic use of cannabidiol (CBD) in intractable epilepsies has increased considerably. Its anticonvulsant properties have been shown in several animal models for acute and chronic epilepsy.

Recent randomized, controlled trials have demonstrated that CBD is superior to placebo in seizure reduction in children with Dravet syndrome and patients with Lennox-Gastaut syndrome. In addition, open label studies indicate that cannabidiol has anticonvulsive properties in a broader range of epilepsy syndromes and etiologies.

In summary, the results of this study provide class III evidence of efficacy and safety of synthetic cannabidiol in children and adults with pharmacoresistant epilepsy. Additional studies investigating efficacy and tolerance of synthetic CBD in larger cohorts are needed.”

https://www.frontiersin.org/articles/10.3389/fneur.2019.01313/full

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Efficacy of cannabidiol in subjects with refractory epilepsy relative to concomitant use of clobazam.

Epilepsy Research“To evaluate the efficacy of open-label, highly purified cannabidiol (CBD, Epidiolex®) in treating refractory epilepsy relative to the concomitant use of clobazam (CLB) as well as the clinical implications of changes in CLB and norclobazam (nCLB) levels.”

“With or without concomitant CLB, CBD may be effective in reducing seizure frequency.”   https://www.sciencedirect.com/science/article/abs/pii/S0920121119303778?via%3Dihub

“With or without concomitant CLB, CBD can be effective in reducing seizure frequency. “

https://www.ncbi.nlm.nih.gov/pubmed/31923763

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Cannabidiol-induced panicolytic-like effects and fear-induced antinociception impairment: the role of the CB1 receptor in the ventromedial hypothalamus.

Image result for Springer Link“The behavioural effects elicited by chemical constituents of Cannabis sativa, such as cannabidiol (CBD), on the ventromedial hypothalamus (VMH) are not well understood. There is evidence that VMH neurons play a relevant role in the modulation of unconditioned fear-related defensive behavioural reactions displayed by laboratory animals.

OBJECTIVES:

This study was designed to explore the specific pattern of distribution of the CB1 receptors in the VMH and to investigate the role played by this cannabinoid receptor in the effect of CBD on the control of defensive behaviours and unconditioned fear-induced antinociception.

METHODS:

A panic attack-like state was triggered in Wistar rats by intra-VMH microinjections of N-methyl-D-aspartate (NMDA). One of three different doses of CBD was microinjected into the VMH prior to local administration of NMDA. In addition, the most effective dose of CBD was used after pre-treatment with the CB1 receptor selective antagonist AM251, followed by NMDA microinjections in the VMH.

RESULTS:

The morphological procedures demonstrated distribution of labelled CB1 receptors on neuronal perikarya situated in dorsomedial, central and ventrolateral divisions of the VMH. The neuropharmacological approaches showed that both panic attack-like behaviours and unconditioned fear-induced antinociception decreased after intra-hypothalamic microinjections of CBD at the highest dose (100 nmol). These effects, however, were blocked by the administration of the CB1 receptor antagonist AM251 (100 pmol) in the VMH.

CONCLUSION:

These findings suggest that CBD causes panicolytic-like effects and reduces unconditioned fear-induced antinociception when administered in the VMH, and these effects are mediated by the CB1 receptor-endocannabinoid signalling mechanism in VMH.”

https://www.ncbi.nlm.nih.gov/pubmed/31919563

https://link.springer.com/article/10.1007%2Fs00213-019-05435-5

“panicolytic: That reduces the flight reflex in animals when faced with danger. Any drug that has this effect.” https://en.wiktionary.org/wiki/panicolytic

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Effects of short-term cannabidiol treatment on response to social stress in subjects at clinical high risk of developing psychosis.

 “Stress is a risk factor for psychosis and treatments which mitigate its harmful effects are needed.

Cannabidiol (CBD) has antipsychotic and anxiolytic effects.

OBJECTIVES:

We investigated whether CBD would normalise the neuroendocrine and anxiety responses to stress in clinical high risk for psychosis (CHR) patients.

RESULTS:

One-way analysis of variance (ANOVA) revealed a significant effect of group (HC, CHR-P, CHR-CBD (p = .005) on cortisol reactivity as well as a significant (p = .003) linear decrease. The change in cortisol associated with experimental stress exposure was greatest in HC controls and least in CHR-P patients, with CHR-CBD patients exhibiting an intermediate response. Planned contrasts revealed that the cortisol reactivity was significantly different in HC compared with CHR-P (p = .003), and in HC compared with CHR-CBD (p = .014), but was not different between CHR-P and CHR-CBD (p = .70). Across the participant groups (CHR-P, CHR-CBD and HC), changes in anxiety and experience of public speaking stress (all p’s < .02) were greatest in the CHR-P and least in the HC, with CHR-CBD participants demonstrating an intermediate level of change.

CONCLUSIONS:

Our findings show that it is worthwhile to design further well powered studies which investigate whether CBD may be used to affect cortisol response in clinical high risk for psychosis patients and any effect this may have on symptoms.”

https://www.ncbi.nlm.nih.gov/pubmed/31915861

“Antipsychotic effects of CBD have been linked to its effects on levels of the endogenous cannabinoid anandamide (AEA) potentially by inhibiting its catalytic enzyme fatty acid amide hydrolase (FAAH). Recent preclinical work has also suggested that CBD may block the anxiogenic effects of chronic stress that was associated with a concomitant decrease in the expression of FAAH following CBD treatment. To the best of our knowledge, this is the first study to have investigated the effects of short-term treatment with CBD on experimentally induced stress in the context of psychosis risk. Notwithstanding its limitations, the present study provides a strong rationale for future studies to investigate whether CBD may have potential to mitigate the harmful effects of stress in the course of daily life by attenuating the altered neuroendocrine and psychological responses to acute stress in CHR participants.”

https://link.springer.com/article/10.1007%2Fs00213-019-05442-6

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