Tag Archives: Delta-9-Tetrahydrocannabinol

Insight of Druggable Cannabinoids against Estrogen Receptor β in Breast Cancer.

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“Breast cancer (BC) is the second most prevalent cancer worldwide.

Estrogen receptor beta (ERβ) is an essential protein of breast cells to suppress estrogen induced uncontrolled proliferation. Thus small molecules that can modulate and enhance ERβ expression would be an effective agent to suppress BC development.

Studies showed that cannabinoid (CB), specifically Delta-9-tetrahydrocannabinol (Del9THC), can increase the expression of ERβ and inhibits BC cell proliferation.

In this study, less psychoactive and structurally similar analogues of Del9THC were chosen as drug candidates and ERβ was targeted as a therapeutic receptor. Delta-8-tetrahydrocannabinol (Del8THC) and Delta-4-Isotetrahydrocannabinol (Del4isoTHC) were the drug candidates selected on the basis of literature reports, Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) properties, medicinal chemistry profile and physicochemical features.

Molecular docking simulations were carried out to determine ligand receptor interactions and binding affinity based on free binding energy. To get a better drug, the structural modification was done on Del8THC and generated a new CB analogue called Cannabinoid A.

Finally, molecular interaction analysis revealed that two CBs and one of their analogue interact with the active site residues of ERβ. Therefore, this study revealed a new way to discover novel drug(s) for BC patients.”

https://www.ncbi.nlm.nih.gov/pubmed/32116130

https://www.tandfonline.com/doi/abs/10.1080/07391102.2020.1737233?journalCode=tbsd20

A Review of Scientific Evidence for THC:CBD Oromucosal Spray (Nabiximols) in the Management of Chronic Pain.

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“The 20% prevalence of chronic pain in the general population is a major health concern given the often profound associated impairment of daily activities, employment status, and health-related quality of life in sufferers. Resource utilization associated with chronic pain represents an enormous burden for healthcare systems. Although analgesia based on the World Health Organization’s pain ladder continues to be the mainstay of chronic pain management, aside from chronic cancer pain or end-of-life care, prolonged use of non-steroidal anti-inflammatory drugs or opioids to manage chronic pain is rarely sustainable.

As the endocannabinoid system is known to control pain at peripheral, spinal, and supraspinal levels, interest in medical use of cannabis is growing.

A proprietary blend of cannabis plant extracts containing delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) as the principal cannabinoids is formulated as an oromucosal spray (USAN name: nabiximols) and standardized to ensure quality, consistency and stability. This review examines evidence for THC:CBD oromucosal spray (nabiximols) in the management of chronic pain conditions.

Cumulative evidence from clinical trials and an exploratory analysis of the German Pain e-Registry suggests that add-on THC:CBD oromucosal spray (nabiximols) may have a role in managing chronic neuropathic pain, although further precise clinical trials are required to draw definitive conclusions.”

https://www.ncbi.nlm.nih.gov/pubmed/32104061

https://www.dovepress.com/a-review-of-scientific-evidence-for-thccbd-oromucosal-spray-nabiximols-peer-reviewed-article-JPR

“Smoked Cannabis Proven Effective In Treating Neuropathic Pain.” https://www.sciencedaily.com/releases/2007/10/071024141745.htm

“Marijuana Relieves Chronic Pain, Research Shows” https://www.webmd.com/pain-management/news/20100830/marijuana-relieves-chronic-pain-research-show#1

Tetrahydrocannabinol and cannabidiol oromucosal spray in resistant multiple sclerosis spasticity: consistency of response across subgroups from the SAVANT randomized clinical trial.

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 Publication Cover“To determine whether differences in disability status, spasticity severity, and spasticity duration at treatment start in patients with resistant multiple sclerosis (MS) spasticity might influence response to add-on tetrahydrocannabinol:cannabidiol (THC:CBD) oromucosal spray (nabiximols) versus further re-adjustment of optimized first-line antispasticity medication.

Methods: Using the database from the Sativex® as Add-on therapy Vs. further optimized first-line ANTispastics (SAVANT) study, this post hoc analysis evaluated spasticity severity (0-10 Numerical Rating Scale [NRS] scores) and pain severity (0-10 NRS scores) evolution from randomization (baseline) to week 12 (end of double-blind treatment) in defined subgroups: Expanded Disability Status Scale [EDSS] score subgroups (< 6 and ≥6); spasticity severity 0-10 NRS score subgroups (4 to ≤6 and >6), and spasticity duration subgroups (< 5 and ≥5 years).

Results: THC:CBD oromucosal spray (nabiximols) halved mean severity scores for spasticity and pain in all subgroups. Active treatment significantly improved mean spasticity severity scores versus placebo from week 4 onwards in both EDSS subgroups, in the severe spasticity subgroup, and in both spasticity duration subgroups. Active treatment significantly improved mean pain severity scores versus placebo in the ≥6 EDSS subgroup, in the severe spasticity subgroup and in both spasticity duration subgroups.

Conclusion: Add-on THC:CBD oromucosal spray (nabiximols) consistently relieves resistant spasticity across subgroups defined by baseline EDSS score, spasticity severity NRS score and spasticity duration. Patients with moderate resistant MS spasticity benefit numerically from treatment; patients with severe resistant spasticity achieve significant therapeutic gains. Spasticity-associated pain often improves similarly in the same subgroups.”

https://www.ncbi.nlm.nih.gov/pubmed/32065006

https://www.tandfonline.com/doi/abs/10.1080/00207454.2020.1730832?journalCode=ines20

Inhibition of autophagic flux differently modulates cannabidiol-induced death in 2D and 3D glioblastoma cell cultures.

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 Scientific Reports“Radiotherapy combined with chemotherapy is the major treatment modality for human glioblastoma multiforme (GBM). GBMs eventually relapse after treatment and the average survival of GBM patients is less than two years.

There is some evidence that cannabidiol (CBD) can induce cell death and increases the radiosensitivity of GBM by enhancing apoptosis. Beside initiation of death, CBD has been demonstrated as an inducer of autophagy.

In the present study, we address the question whether CBD simultaneously induces a protective effect in GBM by upregulating autophagy. Addition of chloroquine that suppressed autophagic flux to 2D GBM cultures increased CBD-induced cell death, presenting proof for the protective autophagy.

Blockage of autophagy upregulated radiation-induced cytotoxicity but only modestly affected the levels of cell death in CBD- or CBD/γ-irradiated 3D GBM cultures. Furthermore, CBD enhanced the pro-apoptotic activities of JNK1/2 and MAPK p38 signaling cascades while partially downregulated the pro-survival PI3K-AKT cascade, thereby changing a balance between cell death and survival.

Suppression of JNK activation partially reduced CBD-induced cell death in 3D GBM cultures. In contrast, co-treatment of CBD-targeted cells with inhibitors of PI3K-AKT-NF-κB, IKK-NF-κB or JAK2-STAT3 pathways killed surviving GBM cells in both 2D and 3D cultures, potentially improving the therapeutic ratio of GBM.”

https://www.ncbi.nlm.nih.gov/pubmed/32060308

“Killing efficiency of cannabinoids (CBD, THC and their combination CBD+THC) against GBM in vitro and in animal experiments has been elucidated in numerous studies during the last 15 years. Additional investigations also confirmed a cytotoxic role of cannabinoids for several other types of cancer. A number of studies demonstrated the efficiency of combined treatments of cannabinoids together with γ-irradiation in both cell culture and in animal experiments.”

https://www.nature.com/articles/s41598-020-59468-4

Cannabinoid receptor expression in non-small cell lung cancer. Effectiveness of tetrahydrocannabinol and cannabidiol inhibiting cell proliferation and epithelial-mesenchymal transition in vitro.

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Image result for plos one “Patients with non-small cell lung cancer (NSCLC) develop resistance to antitumor agents by mechanisms that involve the epithelial-to-mesenchymal transition (EMT). This necessitates the development of new complementary drugs, e.g., cannabinoid receptors (CB1 and CB2) agonists including tetrahydrocannabinol (THC) and cannabidiol (CBD).

The combined use of THC and CBD confers greater benefits, as CBD enhances the effects of THC and reduces its psychotropic activity. We assessed the relationship between the expression levels of CB1 and CB2 to the clinical features of a cohort of patients with NSCLC, and the effect of THC and CBD (individually and in combination) on proliferation, EMT and migration in vitro in A549, H460 and H1792 lung cancer cell lines.

METHODS:

Expression levels of CB1, CB2, EGFR, CDH1, CDH2 and VIM were evaluated by quantitative reverse transcription-polymerase chain reaction. THC and CBD (10-100 μM), individually or in combination (1:1 ratio), were used for in vitro assays. Cell proliferation was determined by BrdU incorporation assay. Morphological changes in the cells were visualized by phase-contrast and fluorescence microscopy. Migration was studied by scratch recolonization induced by 20 ng/ml epidermal growth factor (EGF).

RESULTS:

The tumor samples were classified according to the level of expression of CB1, CB2, or both. Patients with high expression levels of CB1, CB2, and CB1/CB2 showed increased survival reaching significance for CB1 and CB1/CB2 (p = 0.035 and 0.025, respectively).

Both cannabinoid agonists inhibited the proliferation and expression of EGFR in lung cancer cells, and CBD potentiated the effect of THC. THC and CBD alone or in combination restored the epithelial phenotype, as evidenced by increased expression of CDH1 and reduced expression of CDH2 and VIM, as well as by fluorescence analysis of cellular cytoskeleton.

Finally, both cannabinoids reduced the in vitro migration of the three lung cancer cells lines used.

CONCLUSIONS:

The expression levels of CB1 and CB2 have a potential use as markers of survival in patients with NSCLC. THC and CBD inhibited the proliferation and expression of EGFR in the lung cancer cells studied. Finally, the THC/CBD combination restored the epithelial phenotype in vitro.”

https://www.ncbi.nlm.nih.gov/pubmed/32049991

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0228909

Cannabis Sativa Revisited-Crosstalk between microRNA Expression, Inflammation, Oxidative Stress, and Endocannabinoid Response System in Critically Ill Patients with Sepsis.

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cells-logo“Critically ill patients with sepsis require a multidisciplinary approach, as this situation implies multiorgan distress, with most of the bodily biochemical and cellular systems being affected by the condition. Moreover, sepsis is characterized by a multitude of biochemical interactions and by dynamic changes of the immune system. At the moment, there is a gap in our understanding of the cellular, genetic, and molecular mechanisms involved in sepsis.

One of the systems intensely studied in recent years is the endocannabinoid signaling pathway, as light was shed over a series of important interactions of cannabinoid receptors with biochemical pathways, specifically for sepsis. Furthermore, a series of important implications on inflammation and the immune system that are induced by the activity of cannabinoid receptors stimulated by the delta-9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) have been noticed.

One of the most important is their ability to reduce the biosynthesis of pro-inflammatory mediators and the modulation of immune mechanisms. Different studies have reported that cannabinoids can reduce oxidative stress at mitochondrial and cellular levels.

The aim of this review paper was to present, in detail, the important mechanisms modulated by the endocannabinoid signaling pathway, as well as of the molecular and cellular links it has with sepsis. At the same time, we wish to present the possible implications of cannabinoids in the most important biological pathways involved in sepsis, such as inflammation, redox activity, immune system, and epigenetic expression.”

https://www.ncbi.nlm.nih.gov/pubmed/32012914

https://www.mdpi.com/2073-4409/9/2/307

Tetrahydrocannabinol and Cannabidiol Use in an Outpatient Palliative Medicine Population.

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Image result for American Journal of Hospice and Palliative Medicine® “Palliative medicine physicians are challenged by lack of guidance regarding effectiveness and dosing of cannabis products in the setting of their emerging popularity.

OBJECTIVE:

The aim of this study was to describe early patterns of tetrahydrocannabinol (THC) and cannabidiol (CBD) use in Florida following passage of the state’s first medical marijuana law. We describe here the perceived benefits, side effects, and beliefs expressed by patients in a single outpatient academic palliative medicine practice.

RESULTS:

In all, 24% (14/58) of respondents reported THC use, with half using THC on a daily basis. Patients reported improvements in pain, appetite, and nausea. In all, 71% (10/14) began using THC after the diagnosis of their chronic illness, and the most common form of usage was vaping. In all, 24% (14/58) of patients reported CBD use. Patients reported improvements in pain, and the most common form of usage was topical application. None of the patients had used CBD prior to the onset of their chronic illness. In all, 21% (3/14) of THC users and 21% (3/14) of CBD users thought that their substance was helping to cure their illness. Individual reported side effects in both groups were minimal.

CONCLUSIONS:

Approximately a quarter of outpatient palliative care patients use THC or CBD, often on a daily basis. Palliative care providers should be aware of the frequency, diverse usage, and beliefs behind cannabis product use in this patient population.”

https://www.ncbi.nlm.nih.gov/pubmed/31986898

https://journals.sagepub.com/doi/10.1177/1049909119900378

The Role of Cannabidiol (CBD) in Chronic Pain Management: An Assessment of Current Evidence.

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 “Given the growing challenges in chronic pain management coupled with the ongoing consequences of the opioid epidemic, pain management practitioners are looking into more effective, innovative, and safer alternatives to treat pain.

Cannabis-based medicine had been described for hundreds of years but only recently have we seen the more scientific, evidence-based approach to its use, and ongoing investigations continue to explore its potential medical benefits.

While historically more attention has been paid to the psychoactive component of the cannabis plant Δ9-tetrahydrocannabinol (THC), there have been fewer scientific studies on the medical use of the cannabidiol (CBD) – a non-psychoactive component of the cannabis plant.

RECENT FINDINGS:

By examining recent literature, we investigated the use of CBD and its potential role in pain management. Since there are currently no approved pharmaceutical products that contain CBD alone for the management of pain, this review focused on nabiximols (which is a combined product of THC/CBD in a 1:1 ratio) as the only pharmaceutical product available that contains CBD and is being used for the management of pain.

It is difficult to definitely attribute the therapeutic properties to CBD alone since it is always administered with THC.

Based on the available literature, it is difficult to make a recommendation for the use of CBD in chronic pain management. It is also important to note that there are many CBD products currently available as supplements, but these products are non-pharmaceuticals and lack the appropriate clinical studies to support their efficacy claims.”

https://www.ncbi.nlm.nih.gov/pubmed/31980957 

https://link.springer.com/article/10.1007%2Fs11916-020-0835-4

Phytocannabinoids in Neurological Diseases: Could They Restore a Physiological GABAergic Transmission?

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ijms-logo“γ-Aminobutyric acid type A receptors (GABAARs) are the main inhibitory mediators in the central nervous system (CNS). GABAARs are pentameric ligand gated ion channels, and the main subunit composition is usually 2α2βγ, with various isotypes assembled within a set of 19 different subunits. The inhibitory function is mediated by chloride ion movement across the GABAARs, activated by synaptic GABA release, reducing neuronal excitability in the adult CNS. Several studies highlighted the importance of GABA-mediated transmission during neuro-development, and its involvement in different neurological and neurodevelopmental diseases, from anxiety to epilepsy. However, while it is well known how different classes of drugs are able to modulate the GABAARs function (benzodiazepines, barbiturates, neurosteroids, alcohol), up to now little is known about GABAARs and cannabinoids interaction in the CNS. Endocannabinoids and phytocannabinoids are lately emerging as a new class of promising drugs for a wide range of neurological conditions, but their safety as medication, and their mechanisms of action are still to be fully elucidated. In this review, we will focus our attention on two of the most promising molecules (Δ9-tetrahydrocannabinol; Δ9-THC and cannabidiol; CBD) of this new class of drugs and their possible mechanism of action on GABAARs.”

https://www.ncbi.nlm.nih.gov/pubmed/31979108

https://www.mdpi.com/1422-0067/21/3/723

The effect of orally administered dronabinol on optic nerve head blood flow in healthy subjects- a randomized clinical trial.

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Publication cover image“It has been hypothesized that besides its intraocular pressure (IOP) lowering potential, tetrahydrocannabinol (THC) may also improve ocular hemodynamics.

The aim of the present study was to investigate whether single oral administration of dronabinol, a synthetic THC, alters optic nerve head blood flow (ONHBF) and its regulation in healthy subjects.

The study was carried out in a randomized, placebo-controlled, double-masked, two-way crossover design in twenty-four healthy subjects. For each study participant, two study days were scheduled, on which they either received capsules containing 5mg dronabinol or placebo. ONHBF was measured with laser Doppler flowmetry at rest and while the study participants performed isometric exercise for six minutes to increase mean arterial blood pressure (MAP). This was repeated one hour after drug intake. Ocular perfusion pressure (OPP) was calculated as 2/3MAP-IOP.

Dronabinol was well tolerated and no cannabinoid-related psychoactive effects were reported.

Neither administration of dronabinol nor placebo had an effect on IOP, MAP or OPP. In contrast, dronabinol significantly increased ONHBF at rest by 9.5±8.1% whereas placebo did not show a change in ONHBF (0.3±7.4% vs. baseline, p<0.001 between study days). Dronabinol did not alter the autoregulatory response of ONHBF to isometric exercise.

In conclusion, the present data indicate that low dose dronabinol increases ONHBF in healthy subjects without affecting IOP, OPP or inducing psychoactive side effects. In addition, dronabinol does not alter the autoregulatory response of ONHBF to an experimental increase in OPP. Further studies are needed to investigate whether this effect can also be observed in glaucoma patients.”

https://www.ncbi.nlm.nih.gov/pubmed/31977076

https://ascpt.onlinelibrary.wiley.com/doi/abs/10.1002/cpt.1797