Tag Archives: cannabidiol

Direct modulation of the outer mitochondrial membrane channel, voltage-dependent anion channel 1 (VDAC1) by cannabidiol: a novel mechanism for cannabinoid-induced cell death.

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“Cannabidiol (CBD) is a non-psychoactive plant cannabinoid that inhibits cell proliferation and induces cell death of cancer cells and activated immune cells.

Here, we studied the effects of CBD on various mitochondrial functions in BV-2 microglial cells.

Our findings indicate that CBD treatment leads to a biphasic increase in intracellular calcium levels and to changes in mitochondrial function and morphology leading to cell death.

Single-channel recordings of the outer-mitochondrial membrane protein, the voltage-dependent anion channel 1 (VDAC1) functioning in cell energy, metabolic homeostasis and apoptosis revealed that CBD markedly decreases channel conductance.

Finally, using microscale thermophoresis, we showed a direct interaction between purified fluorescently labeled VDAC1 and CBD.

Thus, VDAC1 seems to serve as a novel mitochondrial target for CBD.

The inhibition of VDAC1 by CBD may be responsible for the immunosuppressive and anticancer effects of CBD.”

https://www.ncbi.nlm.nih.gov/pubmed/24309936

“The non-psychoactive plant cannabinoid, cannabidiol (CBD), alone has strong anti-inflammatory and immunosuppressive effects in diverse animal models of disease such as diabetes, cancer, rheumatoid arthritis and multiple sclerosis. In addition, CBD has been reported to have anxiolytic, antiemetic and antipsychotic effects. Moreover, CBD has been shown to possess antitumor activity in human breast carcinoma and to effectively reduce primary tumor mass, as well as size and number of lung metastasis in preclinical animal models of breast cancer.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3877544/

“In summary, in this study we have identified VDAC1 as a new molecular target for CBD. Our study suggests that CBD-induced cell death may occur through the inhibition of VDAC1 conductance and that this interaction may be responsible for the anticancer and immunosuppressive properties of CBD.”

https://www.nature.com/articles/cddis2013471

“Voltage-Dependent Anion Channel 1 As an Emerging Drug Target for Novel Anti-CancerTherapeutics.” https://www.ncbi.nlm.nih.gov/pubmed/28824871

“Finally, small molecules targeting VDAC1 can induce apoptosis. VDAC1 can thus be considered as standing at the crossroads between mitochondrial metabolite transport and apoptosis and hence represents an emerging cancer drug target.”  https://www.ncbi.nlm.nih.gov/pubmed/25448878

Cannabidiol Induces Cytotoxicity and Cell Death via Apoptotic Pathway in Cancer Cell Lines

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“In view of obtaining potential anticancer compounds, we studied the inhibitory activity and the cytotoxic effects of a candidate compound in cancer cells. The cytotoxic effects of cannabidiol (CBD) in vitro were evaluated in NIH3T3 fibroblasts, B16 melanoma cells, A549 lung cancer cells, MDA-MB-231 breast cancer cells, Lenca kidney cells and SNU-C4 colon cancer cells.
The inhibitory activity of CBD was increased in all cancer cells and showed especially strong increment in breast cancer cells. The cytotoxicity of CBD increased in a dose- and time-dependent manner with growth inhibition in all cancer cell lines.
Therefore these results suggest that CBD has a possibility of anticancer agents and anticancer effects against cancer cells by modulation of apoptotic pathway in the range of 5-80 μM concentration.”
https://www.researchgate.net/publication/247915772_Cannabidiol_Induces_Cytotoxicity_and_Cell_Death_via_Apoptotic_Pathway_in_Cancer_Cell_Lines
http://www.biomolther.org/journal/view.html?uid=25&vmd=Full

Phytochemical Aspects and Therapeutic Perspective of Cannabinoids in Cancer Treatment

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Cannabis sativa L. – dried pistillate inflorescences and trichomes on their surface. (a) dried pistillate inflorescences (50% of the size); (b) non‐cystolithic trichome; (c) cystolithic trichome; (d) capitate‐sessile trichome; (e) simple bulbous trichome; (f) capitate‐stalked trichome (400×).

“Cannabis sativa L. (Cannabaceae) is one of the first plants cultivated by man and one of the oldest plant sources of fibre, food and remedies.

Cannabinoids comprise the plant‐derived compounds and their synthetic derivatives as well as endogenously produced lipophilic mediators. Phytocannabinoids are terpenophenolic secondary metabolites predominantly produced in CannabissativaL.

The principal active constituent is delta‐9‐tetrahydrocannabinol (THC), which binds to endocannabinoid receptors to exert its pharmacological activity, including psychoactive effect. The other important molecule of current interest is non‐psychotropic cannabidiol (CBD).

Since 1970s, phytocannabinoids have been known for their palliative effects on some cancer‐associated symptoms such as nausea and vomiting reduction, appetite stimulation and pain relief. More recently, these molecules have gained special attention for their role in cancer cell proliferation and death.

A large body of evidence suggests that cannabinoids affect multiple signalling pathways involved in the development of cancer, displaying an anti‐proliferative, proapoptotic, anti‐angiogenic and anti‐metastatic activity on a wide range of cell lines and animal models of cancer.”

https://www.intechopen.com/books/natural-products-and-cancer-drug-discovery/phytochemical-aspects-and-therapeutic-perspective-of-cannabinoids-in-cancer-treatment

Novel insights into mitochondrial molecular targets of iron-induced neurodegeneration: reversal by cannabidiol.

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“Evidence has demonstrated iron accumulation in specific brain regions of patients suffering from neurodegenerative disorders, and this metal has been recognized as a contributing factor for neurodegeneration.

Using an experimental model of brain iron accumulation, we have shown that iron induces severe memory deficits that are accompanied by oxidative stress, increased apoptotic markers, and decreased synaptophysin in the hippocampus of rats.

The present study aims to characterize iron loading effects as well as to determine the molecular targets of cannabidiol (CBD), the main non-psychomimetic compound of Cannabis sativa, on mitochondria.

Rats received iron in the neonatal period and CBD for 14 days in adulthood. Iron induced mitochondrial DNA (mtDNA) deletions, decreased epigenetic modulation of mtDNA, mitochondrial ferritin levels, and succinate dehydrogenase activity.

CBD rescued mitochondrial ferritin and epigenetic modulation of mtDNA, and restored succinate dehydrogenase activity in iron-treated rats.

These findings provide new insights into molecular targets of iron neurotoxicity and give support for the use of CBD as a disease modifying agent in the treatment of neurodegenerative diseases.”

https://www.ncbi.nlm.nih.gov/pubmed/29374603

Cannabis Use, Lung Cancer, and Related Issues.

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“The cannabis plant and its derivatives have been exploited for centuries for recreational and medicinal purposes with millions of regular users around the world.

The recreational use of cannabis is reflective of its neuropsychiatric effects such as anxiolysis and euphoria. However, cannabis appears to have an emerging therapeutic role, especially in chronic disease and as an adjunct to cancer treatment.

Increasing evidence supports cannabis in the management of chemotherapy induced nausea and vomiting and for pain management, but studies are limited particularly by difficulties associated with standardized dosing estimates and inability to accurately assess biologic activities of compounds in cannabis and derivative products.

Smoking cannabis has not been proven to be a risk factor in the development of lung cancer but the data are limited by small studies, misclassification due to self-reporting of usage, small numbers of heavy cannabis smoking and confounding of risk associated with known causative agents for lung cancer such as parallel chronic tobacco use.

Cannabis and its biologically effective derivatives warrant additional research, ideally controlled trials where the CBD and the THC strength and usage are controlled and documented.”

https://www.ncbi.nlm.nih.gov/pubmed/29374567

“Good News: There’s No Definitive Link Between Marijuana Use and Lung Cancer” http://www.esquire.com/lifestyle/health/news/a52634/marijuana-lung-cancer/ 

“Study Shows No Proven Link Between Weed-Smoking and Lung Cancer”  http://www.complex.com/life/2017/01/weed-study-lung-cancer

Prospects of Cannabidiol for Easing Status Epilepticus-Induced Epileptogenesis and Related Comorbidities.

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Molecular Neurobiology

“The hippocampus is one of the most susceptible regions in the brain to be distraught with status epilepticus (SE) induced injury. SE can occur from numerous causes and is more frequent in children and the elderly population.

Administration of a combination of antiepileptic drugs can abolish acute seizures in most instances of SE but cannot prevent the morbidity typically seen in survivors of SE such as cognitive and mood impairments and spontaneous recurrent seizures. This is primarily due to the inefficiency of antiepileptic drugs to modify the evolution of SE-induced initial precipitating injury into a series of epileptogenic changes followed by a state of chronic epilepsy.

Chronic epilepsy is typified by spontaneous recurrent seizures, cognitive dysfunction, and depression, which are associated with persistent inflammation, significantly waned neurogenesis, and abnormal synaptic reorganization. Thus, alternative approaches that are efficient not only for curtailing SE-induced initial brain injury, neuroinflammation, aberrant neurogenesis, and abnormal synaptic reorganization but also for thwarting or restraining the progression of SE into a chronic epileptic state are needed.

In this review, we confer the promise of cannabidiol, an active ingredient of Cannabis sativa, for preventing or easing SE-induced neurodegeneration, neuroinflammation, cognitive and mood impairments, and the spontaneous recurrent seizures.”

https://www.ncbi.nlm.nih.gov/pubmed/29372545

 https://link.springer.com/article/10.1007%2Fs12035-018-0898-y

Detection and Quantification of Cannabinoids in Extracts of Cannabis sativa Roots Using LC-MS/MS.

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“A liquid chromatography-tandem mass spectrometry single-laboratory validation was performed for the detection and quantification of the 10 major cannabinoids of cannabis, namely, (-)-trans-Δ9-tetrahydrocannabinol, cannabidiol, cannabigerol, cannabichromene, tetrahydrocannabivarian, cannabinol, (-)-trans-Δ8-tetrahydrocannabinol, cannabidiolic acid, cannabigerolic acid, and Δ9-tetrahydrocannabinolic acid-A, in the root extract of Cannabis sativa. Acetonitrile : methanol (80 : 20, v/v) was used for extraction; d3-cannabidiol and d3– tetrahydrocannabinol were used as the internal standards. All 10 cannabinoids showed a good regression relationship with r2 > 0.99. The validated method is simple, sensitive, and reproducible and is therefore suitable for the detection and quantification of these cannabinoids in extracts of cannabis roots. To our knowledge, this is the first report for the quantification of cannabinoids in cannabis roots.”

https://www.ncbi.nlm.nih.gov/pubmed/29359294

https://www.thieme-connect.de/DOI/DOI?10.1055/s-0044-100798

Cannabidiol Limits T Cell–Mediated Chronic Autoimmune Myocarditis: Implications to Autoimmune Disorders and Organ Transplantation

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“Cannabidiol (CBD) is a nonpsychoactive ingredient of marijuana (Cannabis sativa).

Collectively, our study demonstrates that CBD treatment markedly attenuates autoimmune myocarditis and improves myocardial dysfunction and heart failure primarily by its antiinflammatory and antifibrotic effects.

These results, coupled with the proven safety of CBD in human clinical trials and its current orphan drug approval by the FDA for different neurological disorders, suggest that it has tremendous therapeutic potential in the therapy of myocarditis with different etiologies and various autoimmune disorders. The latter is also supported by beneficial effects of CBD in preventing graft versus host disease after allogeneic hematopoietic cell transplantation in a recent phase II human study, as well as in mice with arthritis. Attenuation of the T cell–mediated injury by CBD also suggests that it may have therapeutic utility in management of organ transplantation/rejection.

In conclusion, CBD may represent a promising novel treatment for managing autoimmune myocarditis and possibly other autoimmune disorders and organ transplantation.”

https://www.ncbi.nlm.nih.gov/pubmed/26772776

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5004721/

http://static.smallworldlabs.com/molmedcommunity/content/pdfstore/16_007_Lee.pdf

Cannabidiol for drug-resistant seizures in the Dravet syndrome

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Journal of Paediatrics and Child Health

“Dravet syndrome (severe myoclonic epilepsy of infancy) is characterised by difficult-to-control seizures. Media reports and small clinical trials suggest that cannabidiol, a non-toxic extract of cannabis, can reduce seizure frequency. A recent multicentre randomised controlled trial of 120 children aged 2–18 years with Dravet syndrome supports its efficacy.

Over a 14-week period, children taking 20 mg/kg/day of cannabidiol had a 22.8% reduction (95% confidence interval 5.4–41.1) in seizure frequency compared to a 4-week baseline period. Median convulsive frequency fell from 12.4 to 5.9 per month on cannabidiol, while the placebo group had no change from baseline. No attempt was made to measure non-convulsive seizures (e.g. absences). Subjects took a median of three other anti-convulsant drugs during the trial. Adverse effects were common with cannabidiol, particularly somnolence, fatigue, loss of appetite, vomiting and diarrhoea. Eight patients in the cannabidiol group withdrew compared to one in the placebo group.

Nevertheless, 62% of caregivers in the cannabidiol group felt the patient’s overall condition had improved, using a validated global score, compared to 34% in the placebo group (P = 0.02). Unfortunately, the high rate of adverse events may have led to widespread loss of caregiver blinding, and the study is relatively short term. Nevertheless, the reduction in seizures is clinically relevant, and further longer-term randomised controlled trials are clearly warranted. ” https://www.ncbi.nlm.nih.gov/pubmed/29314377  http://onlinelibrary.wiley.com/doi/10.1111/jpc.13803/full

Practical considerations in medical cannabis administration and dosing.

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European Journal of Internal Medicine

“Cannabis has been employed medicinally throughout history, but its recent legal prohibition, biochemical complexity and variability, quality control issues, previous dearth of appropriately powered randomised controlled trials, and lack of pertinent education have conspired to leave clinicians in the dark as to how to advise patients pursuing such treatment.

With the advent of pharmaceutical cannabis-based medicines (Sativex/nabiximols and Epidiolex), and liberalisation of access in certain nations, this ignorance of cannabis pharmacology and therapeutics has become untenable.

In this article, the authors endeavour to present concise data on cannabis pharmacology related to tetrahydrocannabinol (THC), cannabidiol (CBD) et al., methods of administration (smoking, vaporisation, oral), and dosing recommendations. Adverse events of cannabis medicine pertain primarily to THC, whose total daily dose-equivalent should generally be limited to 30mg/day or less, preferably in conjunction with CBD, to avoid psychoactive sequelae and development of tolerance.

CBD, in contrast to THC, is less potent, and may require much higher doses for its adjunctive benefits on pain, inflammation, and attenuation of THC-associated anxiety and tachycardia. Dose initiation should commence at modest levels, and titration of any cannabis preparation should be undertaken slowly over a period of as much as two weeks.

Suggestions are offered on cannabis-drug interactions, patient monitoring, and standards of care, while special cases for cannabis therapeutics are addressed: epilepsy, cancer palliation and primary treatment, chronic pain, use in the elderly, Parkinson disease, paediatrics, with concomitant opioids, and in relation to driving and hazardous activities.”

https://www.ncbi.nlm.nih.gov/pubmed/29307505
http://www.ejinme.com/article/S0953-6205(18)30004-9/fulltext