Efficacy of the FDA-approved cannabidiol on the development and persistence of temporal lobe epilepsy and complex focal onset seizures

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Experimental Neurology

“Presently there is no drug therapy for curing epilepsy. Despite many advancements in epilepsy research, nearly 30% of people with epilepsy remain refractory to current antiseizure medications (ASM).

Cannabidiol (CBD) has recently been approved as an ASM for pediatric refractory seizures, but it has not been widely tested for adult epileptogenesis and focal onset seizures.

In this study, we investigated the efficacy of the FDA-approved CBD in controlling epileptogenesis and complex focal onset seizures using the mouse kindling model of human temporal lobe epilepsy. We also tested combination regimens of CBD with other ASMs.

The two primary outcome measures were disease modification and suppression of generalized seizures.

In the epileptogenesis study, CBD had a striking effect in attenuating kindling development, with a dose-dependent decrease in behavioral and electrographic seizure activity.

In the retention study, mice previously treated with CBD had significantly reduced overall seizure burden, suggesting disease modification.

In a fully-kindled seizure study, CBD produced rapid and atypical U-shaped dose-dependent protection against generalized seizures (ED50, 52 mg/kg, i.p.).

In a time-course study, CBD showed a maximal protective effect within 1 h of injection, and it declined within 4 h with a biphasic response.

In the combination study, CBD produced synergistic/ additive protection when given with midazolam and ganaxolone, but not with tiagabine, indicating its strong potential as an adjunct ASM. Finally, the protective effects of CBD were not associated with motor and functional impairments.

These preclinical findings demonstrate the potential of adjunct CBD for controlling adult complex focal onset seizure conditions.”

https://pubmed.ncbi.nlm.nih.gov/36216124/

“CBD has strong antiseizure activity in the adult kindling model of epilepsy.. It has a disease-modifying effect by reducing the overall seizure burden.”

https://www.sciencedirect.com/science/article/abs/pii/S0014488622002655?via%3Dihub

Evaluating Cannabis sativa L.’s neuroprotection potential: From bench to bedside

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Phytomedicine

“Background: Neurodegenerative diseases and dementia pose a global health challenge in an aging population, exemplified by the increasing incidence and prevalence of its most common form, Alzheimer’s disease. Although several approved treatments exist for Alzheimer’s disease, they only afford transient symptomatic improvements and are not considered disease-modifying. The psychoactive properties of Cannabis sativa L. have been recognized for thousands of years and now with burgeoning access to medicinal formulations globally, research has turned to re-evaluate cannabis and its myriad phytochemicals as a potential treatment and adjunctive agent for neurodegenerative diseases.

Purpose: This review evaluated the neuroprotective potential of C. sativa’s active constituents for potential therapeutic use in dementia and Alzheimer’s disease, based on published studies demonstrating efficacy in experimental preclinical settings associated with neurodegeneration.

Study design: Relevant information on the neuroprotective potential of the C. sativa’s phytoconstituents in preclinical studies (in vitro, in vivo) were included. The collated information on C. sativa’s component bioactivity was organized for therapeutic applications against neurodegenerative diseases.

Methods: The therapeutic use of C. sativa related to Alzheimer’s disease relative to known phytocannabinoids and other phytochemical constituents were derived from online databases, including PubMed, Elsevier, The Plant List (TPL, www.theplantlist.org), Science Direct, as well as relevant information on the known pharmacological actions of the listed phytochemicals.

Results: Numerous C. sativa -prevalent phytochemicals were evidenced in the body of literature as having efficacy in the treatment of neurodegenerative conditions exemplified by Alzheimer’s disease. Several phytocannabinoids, terpenes and select flavonoids demonstrated neuroprotection through a myriad of cellular and molecular pathways, including cannabinoid receptor-mediated, antioxidant and direct anti-aggregatory actions against the pathological toxic hallmark protein in Alzheimer’s disease, amyloid β.

Conclusions: These findings provide strong evidence for a role of cannabis constituents, individually or in combination, as potential neuroprotectants timely to the emergent use of medicinal cannabis as a novel treatment for neurodegenerative diseases. Future randomized and controlled clinical studies are required to substantiate the bioactivities of phytocannabinoids and terpenes and their likely synergies.”

https://pubmed.ncbi.nlm.nih.gov/36209703/

https://www.sciencedirect.com/science/article/abs/pii/S0944711322005748?via%3Dihub

Role of the endocannabinoid system in the pathophysiology of endometriosis and therapeutic implications

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“Endometriosis patients experience debilitating chronic pain, and the first-line treatment is ineffective at managing symptoms. Although surgical removal of the lesions provides temporary relief, more than 50% of the patients experience disease recurrence. Despite being a leading cause of hysterectomy, endometriosis lacks satisfactory treatments and a cure. Another challenge is the poor understanding of disease pathophysiology which adds to the delays in diagnosis and overall compromised quality of life. Endometriosis patients are in dire need of an effective therapeutic strategy that is both economical and effective in managing symptoms, while fertility is unaffected.

Endocannabinoids and phytocannabinoids possess anti-inflammatory, anti-nociceptive, and anti-proliferative properties that may prove beneficial for endometriosis management, given that inflammation, vascularization, and pain are hallmark features of endometriosis.

Endocannabinoids are a complex network of molecules that play a central role in physiological processes including homeostasis and tissue repair, but endocannabinoids have also been associated in the pathophysiology of several chronic inflammatory diseases including endometriosis and cancers. The lack of satisfactory treatment options combined with the recent legalization of recreational cannabinoids in some parts of the world has led to a rise in self-management strategies including the use of cannabinoids for endometriosis-related pain and other symptoms.

In this review, we provide a comprehensive overview of endocannabinoids with a focus on their potential roles in the pathophysiology of endometriosis. We further provide evidence-driven perspectives on the current state of knowledge on endometriosis-associated pain, inflammation, and therapeutic avenues exploiting the endocannabinoid system for its management.”

https://pubmed.ncbi.nlm.nih.gov/36207747/

https://jcannabisresearch.biomedcentral.com/articles/10.1186/s42238-022-00163-8

Therapeutic and clinical foundations of cannabidiol therapy for difficult-to-treat seizures in children and adults with refractory epilepsies

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Experimental Neurology

“Novel and effective antiseizure medications are needed to treat refractory and rare forms of epilepsy.

Cannabinoids, which are obtained from the cannabis plant, have a long history of medical use, including for neurologic conditions. In 2018, the US Food and Drug Administration approved the first phytocannabinoid, cannabidiol (CBD, Epidiolex®), which is now indicated for severe seizures associated with three rare forms of developmental and epileptic encephalopathy: Dravet syndrome, Lennox-Gastaut syndrome, and tuberous sclerosis complex.

Compelling evidence supports the efficacy of CBD in experimental models and patients with epilepsy. In randomized clinical trials, highly-purified CBD has demonstrated efficacy with an acceptable safety profile in children and adults with difficult-to-treat seizures. Although the underlying antiseizure mechanisms of CBD in humans have not yet been elucidated, the identification of novel antiseizure targets of CBD preclinically indicates multimodal mechanisms that include non-cannabinoid pathways.

In addition to antiseizure effects, CBD possesses strong anti-inflammatory and neuroprotective activities, which might contribute to protective effects in epilepsy and other conditions. This article provides a succinct overview of therapeutic approaches and clinical foundations of CBD, emphasizing the clinical utility of CBD for the treatment of seizures associated with refractory and rare epilepsies.

CBD has shown to be a safe and effective antiseizure medicine, demonstrating a broad spectrum of efficacy across multiple seizure types, including those associated with severe epilepsies with childhood onset.

Despite such promise, there are many perils with CBD that hampers its widespread use, including limited understanding of pharmacodynamics, limited exposure-response relationship, limited information for seizure freedom with continued use, complex pharmacokinetics with drug interactions, risk of adverse effects, and lack of expert therapeutic guidelines. These scientific issues need to be resolved by further investigations, which would decide the unique role of CBD in the management of refractory epilepsy.”

https://pubmed.ncbi.nlm.nih.gov/36206806/

https://www.sciencedirect.com/science/article/pii/S001448862200262X?via%3Dihub

Clinical efficacy and safety of cannabidiol for pediatric refractory epilepsy indications: A systematic review and meta-analysis

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Experimental Neurology

“Antiseizure medications (ASMs) are the mainstay for the treatment of seizure disorders. However, about one-third of people with epilepsy remain refractory to current ASMs.

Cannabidiol (CBD) has recently been approved as ASM for three refractory seizure indications in children and adults. In this study, we evaluated the overall clinical potential of oral CBD to treat refractory epilepsy in patients with Dravet syndrome (DS), Lennox-Gastaut syndrome (LGS), and tuberous sclerosis complex (TSC) through a systematic review and meta-analysis. A comprehensive search of databases was conducted, including randomized controlled trials (RCTs) assessing the effect of CBD in epilepsy patients. The review was conducted as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The review focused on RCTs involving patients receiving highly purified oral CBD (Epidiolex, 10 to 50 mg/kg/day) for up to 14 weeks. A subgroup analysis by syndrome and CBD with or without clobazam was conducted.

The key outcomes were reduction in seizure frequency, adverse events, and interactions with clobazam as co-therapy. Odds ratio (OR) with 95% confidence interval (CI) were estimated. Of 1183 articles screened, we included 6 RCTs meeting our eligibility criteria. All studies were considered to have a low risk of bias. In the pooled analysis, CBD treatment was found to be significantly efficacious compared to placebo (OR = 2.45, 95% CI =1.81-3.32, p < 0.01). Subgroup analysis by syndrome demonstrated the odds of ≥50% reduction in seizures with CBD treatment in patients with DS (OR = 2.26, 95% CI:1.38-3.70), LGS (OR = 2.98, 95% CI:1.83-4.85) and TSC (OR = 1.99, 95% CI = 1.06-3.76). Compared with placebo, CBD was associated with increased adverse events (OR = 1.81, 95% CI = 1.33-2.46) such as diarrhea, somnolence, and sedation, and any serious adverse events (OR = 2.86, 95% CI = 1.63-5.05). Other factors, including dosage and clobazam co-therapy, were significantly associated with a greater effect on seizure control and side effects of CBD.

In conclusion, the study shows that CBD is highly efficacious both as standalone and adjunct therapy with clobazam for controlling seizures in DS, LGS, and TSC conditions while limiting side effects. Further pharmacodynamic investigation of CBD actions, drug interaction assessment, and therapeutic management guidelines are warranted.”

https://pubmed.ncbi.nlm.nih.gov/36206805/

“CBD is effective for all three refractory seizure indications.”

https://www.sciencedirect.com/science/article/abs/pii/S0014488622002631?via%3Dihub

Medical cannabis dimethyl ether, ethanol and butane extracts inhibit the in vitro growth of bacteria and dermatophytes causing common skin diseases

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Frontiers - Crunchbase Company Profile & Funding

“Cannabis preparations are gaining popularity among patients with various skin diseases. Due to the lack of scientific evidence, dermatologists remain cautious about their prescriptions. So far, only a few studies have been published about the effects of high-potency cannabis extracts on microorganisms (especially dermatophytes) causing skin problems that affect more than 25% of the worldwide population. Even though, the high-potency cannabis extracts prepared by cold extraction are mostly composed of non-psychoactive tetrahydrocannabinolic acid (THCA) and only low amount of THC, their use in topical treatment can be stigmatized. The in vitro antimicrobial and antifungal activity of two high potent cannabis strains extracted by three solvents traditionally or currently used by cannabis users (ethanol; EtOH, butane; BUT, dimethyl ether; DME) was investigated by broth dilution method. The chemical profile of cannabis was determined by high-performance liquid chromatography with ultraviolet detection and gas chromatography with mass spectrometer and flame ionization detector. The extraction methods significantly influenced chemical profile of extracts. The yield of EtOH extracts contained less cannabinoids and terpenes compared to BUT and DME ones. Most of the extracts was predominantly (>60%) composed of various cannabinoids, especially THCA. All of them demonstrated activity against 18 of the 19 microorganisms tested. The minimal inhibitory concentrations (MICs) of the extracts ranged from 4 to 256 μg/mL. In general, the bacteria were more susceptible to the extracts than dermatophytes. Due to the lower content of biologically active substances, the EtOH extracts were less effective against microorganisms. Cannabis extracts may be of value to treat dermatophytosis and other skin diseases caused by various microorganisms. Therefore, they could serve as an alternative or supportive treatment to commonly used antibiotics.”

https://pubmed.ncbi.nlm.nih.gov/36204633/

“Our research brought new evidence that cannabis extracts may be of value to treat dermatophytosis and other skin diseases caused by various microorganisms and showed that cannabis could serve as an alternative or supportive treatment to commonly used antibiotics.”

https://www.frontiersin.org/articles/10.3389/fmicb.2022.953092/full

Patient-Related Barriers to the Prescription of Cannabinoid-Based Medicines in Palliative Care: A Qualitative Approach

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“Background: A minority of palliative care patients benefit from prescribed cannabinoid-based medicines (CBMs).

Objective: The objective of this study was to explore the perceptions, expectations, and experiences of CBM usage among palliative care patients and to evaluate whether and how they may constitute an obstacle to prescription.

Design: This is a qualitative study involving semistructured in-depth interviews with 10 patients hospitalized in a palliative care unit in Geneva, Switzerland. The data were analyzed using the interpretative phenomenological analysis method.

Results: Semistructured interviews were conducted on 10 patients (average age of 73.3 years), mainly with advanced cancer. Most patients favored CBM use in palliative care and distinguished it from recreational use. Seven themes were identified from patients’ perceptions, experiences, and expectations during the interviews: right time to begin CBMs, off-label use, information about side effects, lack of a safe medical framework, costs, relatives, and social acceptance of CBMs.

Conclusion: The obstacles described by the patients seem to be surmountable with specific measures at the clinical level. We suggest training health professionals in a palliative care setting, especially in explaining the effects and side effects. CBMs will undoubtedly play a more significant role in palliative care medicine in the years to come.”

https://pubmed.ncbi.nlm.nih.gov/36203714/

https://www.liebertpub.com/doi/10.1089/pmr.2022.0021

[Low-dose THC in geriatric and palliative patients]

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“Background: Cannabis-containing medicines have been successfully used in our practice for more than 20 years in pain and especially in geriatric and palliative patients. While it was initially a very indication-specific use (pain, loss of appetite, etc.) and also with higher THC doses, this changed over time to low THC doses and a therapy focus on suffering-perpetuating symptoms and especially on stress (Matrix of Symptoms).

Method: As part of the legally prescribed companion survey, we evaluated our data in parallel and discussed it publicly in a series of publications. Based on these published results, the article is intended to show an overview of our experiences.

Results: Low-dose THC has a positive effect on morbidity, side effects, quality of life and mortality in geriatric and palliative patients.

Conclusion: Early therapy is particularly appropriate in geriatric and palliative patients due to the clear benefit-risk ratio of low-dose THC.”

https://pubmed.ncbi.nlm.nih.gov/36195786/

Identification of CB1 Ligands among Drugs, Phytochemicals and Natural-Like Compounds: Virtual Screening and In Vitro Verification

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“Cannabinoid receptor type 1 (CB1) is an important modulator of many key physiological functions and thus a compelling molecular target. However, safe CB1 targeting is a non-trivial task. In recent years, there has been a surge of data indicating that drugs successfully used in the clinic for years (e.g. paracetamol) show CB1 activity. Moreover, there is a lot of promise in finding CB1 ligands in plants other than Cannabis sativa. In this study, we searched for possible CB1 activity among already existing drugs, their metabolites, phytochemicals, and natural-like molecules. We conducted two iterations of virtual screening, verifying the results with in vitro binding and functional assays. The in silico procedure consisted of a wide range of structure- and ligand-based methods, including docking, molecular dynamics, and quantitative structure-activity relationship (QSAR). As a result, we identified travoprost and ginkgetin as CB1 ligands, which provides a starting point for future research on the impact of their metabolites or preparations on the endocannabinoid system. Moreover, we found five natural-like compounds with submicromolar or low micromolar affinity to CB1, including one mixed partial agonist/antagonist viable for hit-to-lead phase. Finally, the computational procedure established in this work will be of use for future screening campaigns for novel CB1 ligands.”

https://pubmed.ncbi.nlm.nih.gov/36197801/

https://pubs.acs.org/doi/10.1021/acschemneuro.2c00502

Cannabinoids in hyperhidrosis

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“Hyperhidrosis can significantly curtail patient quality of life, from debilitating physical symptoms to social stigmatization and reduced life opportunities. Current treatments often prove unsatisfactory, especially in sufferers of generalized hyperhidrosis. In this open trial, we present the case of a refractory generalized hyperhidrosis treated with cannabinoids. We found a remarkable reduction in the volume of sweat and an improvement to the patient’s quality of life using this novel low-cost and low-impact approach.”

https://pubmed.ncbi.nlm.nih.gov/36200741/

https://www.tandfonline.com/doi/full/10.1080/09546634.2022.2127308?scroll=top&needAccess=true