Author Archives: David Worrell

The Interplay between the Immune and the Endocannabinoid Systems in Cancer

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cells-logo“The therapeutic potential of Cannabis sativa has been recognized since ancient times. Phytocannabinoids, endocannabinoids and synthetic cannabinoids activate two major G protein-coupled receptors, subtype 1 and 2 (CB1 and CB2). Cannabinoids (CBs) modulate several aspects of cancer cells, such as apoptosis, autophagy, proliferation, migration, epithelial-to-mesenchymal transition and stemness. Moreover, agonists of CB1 and CB2 receptors inhibit angiogenesis and lymphangiogenesis in vitro and in vivo. Low-grade inflammation is a hallmark of cancer in the tumor microenvironment (TME), which contains a plethora of innate and adaptive immune cells. These cells play a central role in tumor initiation and growth and the formation of metastasis. CB2 and, to a lesser extent, CB1 receptors are expressed on a variety of immune cells present in TME (e.g., T cells, macrophages, mast cells, neutrophils, NK cells, dendritic cells, monocytes, eosinophils). The activation of CB receptors modulates a variety of biological effects on cells of the adaptive and innate immune system. The expression of CB2 and CB1 on different subsets of immune cells in TME and hence in tumor development is incompletely characterized. The recent characterization of the human cannabinoid receptor CB2-Gi signaling complex will likely aid to design potent and specific CB2/CB1 ligands with therapeutic potential in cancer.”

https://pubmed.ncbi.nlm.nih.gov/34064197/

https://www.mdpi.com/2073-4409/10/6/1282

Effects of tetrahydrocannabinols on human oral cancer cell proliferation, apoptosis, autophagy, oxidative stress, and DNA damage

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Archives of Oral Biology“Cannabinoids, including delta-8- and delta-9-tetrahydrocannabinol (THC) have a palliative care impact and may therefore be beneficial against cancer.

The aim of this study was to investigate the effect of Δ9-THC and Δ8-THC on oral cancer cell behaviors.

Results: Both cannabinoids were found to decrease cell viability/proliferation by blocking the cell cycle progression from the S to the G2/M phase and enhancing their apoptosis and autophagy. Δ9-THC and Δ8-THC also suppressed the migration/invasion by inhibiting epithelial-mesenchymal transition markers, such as E-cadherin, in addition to decreasing reactive oxygen species (ROS) production and increasing glutathione (GSH) and the expression of mtMP. Δ9-THC and Δ8-THC also downregulated cyclin D1, p53, NOXA, PUMAα, and DRAM expressions but increased p21 and H2AX expression.

Conclusion: We demonstrated that cannabinoids (Δ9-THC and Δ8-THC) were able to decrease oral cancer cell growth through various mechanisms, including apoptosis, autophagy, and oxidative stress. These results suggest a potential use of these molecules as a therapy against oral cancer.”

https://pubmed.ncbi.nlm.nih.gov/34146926/

“Cannabinoids (Δ9-THC and Δ8-THC) decrease oral cancer cell viability/ proliferation.”

https://www.sciencedirect.com/science/article/abs/pii/S0003996921001631?via%3Dihub

A Phase 2 Randomised Clinical Trial Assessing the Tolerability of Two Different Ratios of Medicinal Cannabis in Patients With High Grade Gliomas

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Frontiers in Oncology (@FrontOncology) | Twitter“Background: Cannabis for cancer is very topical and, given the use of illicit cannabis preparations used in this vulnerable population, research investigating standardised, quality-assured medicinal cannabis is critical to inform clinicians and assist patient safety.

Methods: A randomized trial involving adult patients diagnosed with a high-grade glioma, no history of substance abuse, liver or kidney damage or myocardial infarction were eligible for inclusion in a tolerability study on two different ratios of medicinal cannabis. Baseline screening of brain morphology, blood pathology, functional status, and cognition was conducted. A retrospective control group was used for comparison for secondary outcomes.

Results: Participants (n=88) were on average 53.3 years old. A paired t-test assessed the Functional Assessment of Cancer Therapy for Brain Cancer (FACT-Br) between groups from baseline to week 12 found that the 1:1 ratio favoured both physical (p=0.025) and functional (p=0.014) capacity and improved sleep (p=0.009). Analysis of changes from baseline to week 12 also found 11% of 61 participants had a reduction in disease, 34% were stable, 16% had slight enhancement, and 10% had progressive disease. No serious adverse events occurred. Side effects included dry mouth, tiredness at night, dizziness, drowsiness.

Conclusion: This study demonstrated that a single nightly dose of THC-containing medicinal cannabis was safe, had no serious adverse effects and was well tolerated in patients. Medicinal cannabis significantly improved sleep, functional wellbeing, and quality of life.”

https://pubmed.ncbi.nlm.nih.gov/34094937/

“From this study we have shown that a single nightly dose of THC-containing cannabis was well tolerated in patients in both groups with high-grade gliomas and significantly improved sleep, functional wellbeing and contentment with QoL in a sample of patients compared to baseline. From this trial, the 1:1 ratio has been identified as the preferred combination the moving forward to further trials. This study significantly informs MC product choice for ongoing studies into cannabis being a potential adjunct treatment option for this patient population.”

https://www.frontiersin.org/articles/10.3389/fonc.2021.649555/full

Prolonged Medical Cannabis Treatment is Associated With Quality of Life Improvement and Reduction of Analgesic Medication Consumption in Chronic Pain Patients

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Frontiers in Pharmacology (@FrontPharmacol) | Twitter“Introduction: Chronic non-cancer pain (CNCP) is one of the most prevalent indications for medical cannabis (MC) treatment globally. In this study, we investigated CNCP parameters in patients during prolonged MC treatment, and assessed the interrelation between CNCP parameters and the chemical composition of MC chemovar used. 

Methods: A cross-sectional questionnaire-based study was performed in one-month intervals for the duration of six months. Subjects were adult patients licensed for MC treatment who also reported a diagnosis of CNCP by a physician. Data included self-reported questionnaires. MC treatment features included administration route, cultivator, cultivar name and monthly dose. Comparison statistics were used to evaluate differences between the abovementioned parameters and the monthly MC chemovar doses at each time point. 

Results: 429, 150, 98, 71, 77 and 82 patients reported fully on their MC treatment regimens at six one-month intervals, respectively. Although pain intensities did not change during the study period, analgesic medication consumption rates decreased from 46 to 28% (p < 0.005) and good Quality of Life (QoL) rates increased from 49 to 62% (p < 0.05). These changes overlapped with increase in rates of (-)-Δ9–trans-tetrahydrocannabinol (THC) and α-pinene high dose consumption. 

Conclusion: Even though we observed that pain intensities did not improve during the study, QoL did improve and the rate of analgesic medication consumption decreased alongside with increasing rates of high dose THC and α-pinene consumption. Understanding MC treatment composition may shed light on its long-term effects.”

https://pubmed.ncbi.nlm.nih.gov/34093173/

“In this study, although pain intensities did not change under long-term MC treatment, analgesic medication consumption rates decreased and ‘better’ QoL rates increased. These changes coincided with the increased rates of patients’ consumption of high dose THC and α pinene. These results may shed light on the long-term beneficial effects of MC on CNCP.”

https://www.frontiersin.org/articles/10.3389/fphar.2021.613805/full

Cannabinoid-based therapy as a future for joint degeneration. Focus on the role of CB 2 receptor in the arthritis progression and pain: an updated review

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“Over the last several decades, the percentage of patients suffering from different forms of arthritis has increased due to the ageing population and the increasing risk of civilization diseases, e.g. obesity, which contributes to arthritis development. Osteoarthritis and rheumatoid arthritis are estimated to affect 50-60% of people over 65 years old and cause serious health and economic problems. Currently, therapeutic strategies are limited and focus mainly on pain attenuation and maintaining joint functionality. First-line therapies are nonsteroidal anti-inflammatory drugs; in more advanced stages, stronger analgesics, such as opioids, are required, and in the most severe cases, joint arthroplasty is the only option to ensure joint mobility.

Cannabinoids, both endocannabinoids and synthetic cannabinoid receptor (CB) agonists, are novel therapeutic options for the treatment of arthritis-associated pain. CB1 receptors are mainly located in the nervous system; thus, CB1 agonists induce many side effects, which limit their therapeutic efficacy. On the other hand, CB2 receptors are mainly located in the periphery on immune cells, and CB2 modulators exert analgesic and anti-inflammatory effects in vitro and in vivo. In the current review, novel research on the cannabinoid-mediated analgesic effect on arthritis is presented, with particular emphasis on the role of the CB2 receptor in arthritis-related pain and the suppression of inflammation.”

https://pubmed.ncbi.nlm.nih.gov/34050525/

“Cannabinoids not only alleviate joint hyperalgesia but also may help to prevent joint damage, chronic pain development and disease progression.”

https://link.springer.com/article/10.1007/s43440-021-00270-y

A Large-Scale Naturalistic Examination of the Acute Effects of Cannabis on Pain

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View details for Cannabis and Cannabinoid Research cover image“Cannabis use for pain relief is commonly reported, yet laboratory studies and clinical trials suggest that cannabinoids are weak analgesics, and it is unclear whether perceived reductions in pain from before to after cannabis use relate to factors such as dose, method of administration, phytocannabinoid content, or the age or gender of the user. We determined whether inhalation of cannabis decreased self-reported pain ratings as well as whether user gender, age, time, method of administration, tetrahydrocannabinol (THC)/cannabidiol (CBD) content, or dose of cannabis contribute to changes in these ratings. We also examined whether tolerance may develop to the analgesic effects of cannabis over time.

Results: For all three pain symptoms, severity ratings decreased significantly after cannabis use. Women reported higher baseline and postcannabis pain severity than did men, and men reported larger decreases in pain than did women. Neither THC nor CBD content nor their interaction predicted reductions in pain ratings. However, vaping was associated with larger reductions in joint pain ratings than was smoking, and lower doses were associated with larger reductions in nerve pain ratings. Additionally, for all three pain symptoms, the dose of cannabis used to manage pain increased significantly over time.

Conclusions: Inhaled cannabis reduces self-reported pain severity by ∼42–49%. However, these reductions appear to diminish across time, and patients use larger doses across time, suggesting that analgesic tolerance develops with continued use.”

https://www.liebertpub.com/doi/abs/10.1089/can.2020.0068?journalCode=can

“Inhaled Cannabis Associated with Significant Reductions in Self-Reported Pain Severity”

β-Caryophyllene, A Natural Dietary CB2 Receptor Selective Cannabinoid can be a Candidate to Target the Trinity of Infection, Immunity, and Inflammation in COVID-19

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Frontiers in Pharmacology (@FrontPharmacol) | Twitter“Coronavirus disease (COVID-19), caused by novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is an ongoing pandemic and presents a public health emergency. It has affected millions of people and continues to affect more, despite tremendous social preventive measures. Identifying candidate drugs for the prevention and treatment of COVID-19 is crucial. The pathogenesis and the complications with advanced infection mainly involve an immune-inflammatory cascade. Therefore, therapeutic strategy relies on suppressing infectivity and inflammation, along with immune modulation.

One of the most promising therapeutic targets for the modulation of immune-inflammatory responses is the endocannabinoid system, particularly the activation of cannabinoid type 2 receptors (CB2R), a G-protein coupled receptor which mediates the anti-inflammatory properties by modulating numerous signaling pathways. To pharmacologically activate the CB2 receptors, a naturally occurring cannabinoid ligand, beta-caryophyllene (BCP), received attention due to its potent anti-inflammatory, antiviral, and immunomodulatory properties. BCP is recognized as a full selective functional agonist on CB2 receptors and produces therapeutic effects by activating CB2 and the nuclear receptors, peroxisome proliferator-activated receptors (PPARs).

BCP is regarded as the first dietary cannabinoid with abundant presence across cannabis and non-cannabis plants, including spices and other edible plants. BCP showed tissue protective properties and favorably modulates numerous signaling pathways and inhibits inflammatory mediators, including cytokines, chemokines, adhesion molecules, prostanoids, and eicosanoids. Based on its pharmacological properties, molecular mechanisms, and the therapeutic potential of BCP as an immunomodulator, anti-inflammatory, organ-protective, and antiviral, we hypothesize that BCP could be a promising therapeutic and/or preventive candidate to target the triad of infection, immunity, and inflammation in COVID-19. In line with numerous studies that proposed the potential of cannabinoids in COVID-19,

BCP may be a novel candidate compound for pharmaceutical and nutraceutical development due to its unique functional receptor selectivity, wide availability and accessibility, dietary bioavailability, nonpsychoactivity, and negligible toxicity along with druggable properties, including favorable pharmacokinetic and physicochemical properties. Based on reasonable pharmacological mechanisms and therapeutic properties, we speculate that BCP has potential to be investigated against COVID-19 and will inspire further preclinical and clinical studies.”

https://pubmed.ncbi.nlm.nih.gov/34054510/

“Over the past few months, it has been suggested that modulation of the endocannabinoid system by cannabinoids, including cannabidiol, could be useful in prophylaxis and treatment of COVID-19 and may improve prognosis. Recently, extract of Cannabis sativa containing phytocannabinoids and terpenes were shown to modulate the inflammatory mediators in alveolar epithelial cells (A549) in COVID-19-associated inflammation and suggested that the phytocannabinoid mix formulation exerted better activity in comparison with individual fractions from cannabis. Many cannabinoids, including cannabidiol, have been suggested for their possible potential as preventive agents or therapeutic adjuvants with other agents in targeting the trinity of infection, inflammation, and immunity in COVID-19.”

https://www.frontiersin.org/articles/10.3389/fphar.2021.590201/full

“β-caryophyllene (BCP) is a common constitute of the essential oils of numerous spice, food plants and major component in Cannabis.”   http://www.ncbi.nlm.nih.gov/pubmed/23138934

“Beta-caryophyllene is a dietary cannabinoid.”   https://www.ncbi.nlm.nih.gov/pubmed/18574142

Cannabidiol Modulates Mitochondrial Redox and Dynamics in MCF7 Cancer Cells: A Study Using Fluorescence Lifetime Imaging Microscopy of NAD(P)H

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Archive of "Frontiers in Molecular Biosciences".“The cannabinoid, cannabidiol (CBD), is part of the plant’s natural defense system that when given to animals has many useful medicinal properties, including activity against cancer cells, modulation of the immune system, and efficacy in epilepsy.

Our results support the use of NAD(P)H autofluorescence as an investigative tool and provide further evidence that CBD can modulate mitochondrial function and morphology in a dose-dependent manner, with clear evidence of it inducing oxidative stress at higher concentrations.

This continues to support emerging data in the literature and may provide further insight into its overall mode of action, not only in cancer, but potentially its function in the plant and why it can act as a medicine.”

https://pubmed.ncbi.nlm.nih.gov/34046425/

“Uncontrolled cell growth, or cancer, is frequently associated with increased aerobic glycolysis (the Warburg effect) and alterations in mitochondrial function.

A plant’s ability to develop tumors could explain why so many secondary plant phenolic compounds appear to have anticancer activity in both plant and animal models; over 3,000 species of plants have anticancer activity in animals, with many modulating mitochondrial function and apoptosis

CBD, along with Δ9-tetrahydrocannabinol (THC), is a major phytocannabinoid and both are well described components of medicines.

A growing number of studies have demonstrated the anticancer properties of CBD, in both in vitro and in vivo models.”

https://www.frontiersin.org/articles/10.3389/fmolb.2021.630107/full

Cannabis and cannabinoid use in autism spectrum disorder: a systematic review

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SciELO (Scientific Electronic Library Online) | UOC Library“Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by persistent deficits in social communication and social interaction, associated with the presence of restricted and repetitive patterns of behavior, interests, or activities. Cannabis has been used to alleviate symptoms associated with ASD.

Method: We carried out a systematic review of studies that investigated the clinical effects of cannabis and cannabinoid use on ASD, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA checklist). The search was carried out in four databases: MEDLINE/PubMed, Scientific Electronic Library Online (SciELO), Scopus, and Web of Science. No limits were established for language during the selection process. Nine studies were selected and analyzed.

Results: Some studies showed that cannabis products reduced the number and/or intensity of different symptoms, including hyperactivity, attacks of self-mutilation and anger, sleep problems, anxiety, restlessness, psychomotor agitation, irritability, aggressiveness perseverance, and depression. Moreover, they found an improvement in cognition, sensory sensitivity, attention, social interaction, and language. The most common adverse effects were sleep disorders, restlessness, nervousness and change in appetite.

Conclusion: Cannabis and cannabinoids may have promising effects in the treatment of symptoms related to ASD, and can be used as a therapeutic alternative in the relief of those symptoms. However, randomized, blind, placebo-controlled clinical trials are necessary to clarify findings on the effects of cannabis and its cannabinoids in individuals with ASD.”

https://pubmed.ncbi.nlm.nih.gov/34043900/

 

“Cannabis and cannabinoids have very promising effects in the treatment of autistic symptoms and can be used in the future as an important therapeutic alternative to relieve those symptoms, especially bouts of self-mutilation and anger, hyperactivity, sleep problems, anxiety, restlessness, psychomotor agitation, irritability, and aggressiveness; as well as improve sensory sensitivity, cognition, attention, social interaction, language, perseverance, and depression.”

https://www.scielo.br/j/trends/a/LBmJK6d8bqr5jVK6fp3CHXt/?lang=en

Topical Cannabis-Based Medicines – A Novel Adjuvant Treatment for Venous Leg Ulcers: An Open-Label Trial

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“Venous Leg Ulcers are highly prevalent lower limb integumentary wounds that remain challenging to heal despite the use of evidence-based compression therapies. A multitude of adjuvant treatments have been studied but none have demonstrated enough efficacy to gain adoption into treatment guidelines.

Global attention on cannabis-based therapies is increasing and has been driven by quantum scientific advancements in the understanding of the endocannabinoid signalling system. Topical Cannabis-Based Medicines represent a novel treatment paradigm for venous leg ulcers in terms of promoting wound closure.

Fourteen complex patients with sixteen recalcitrant leg ulcers were treated with Topical Cannabis-Based Medicines in conjunction with compression bandaging, every second day, to both wound bed and peri-wound tissues. The cohort had a mean age of 75.8 years and was medically complex as reflected by a mean M3 multimorbidity index score of 2.94 and a mean Palliative Performance Scale score of 67.1%.

Complete wound closure, defined being fully epithelialized, was achieved among 11 patients (79%) and 13 wounds (81%) within a median of 34 days. All three remaining patients demonstrated progressive healing trends but were lost to follow-up. The treatments were well tolerated, and no significant adverse reactions were experienced.

The rapid wound closure of previously non-healing venous leg ulcers among elderly and highly complex patients suggests that Topical Cannabis-Based Medicines may become effective adjuvants in conjunction with compression therapy. This may also indicate that they may have an even broader role within integumentary and wound management. Therefore, this treatment paradigm warrants being subjected to controlled trials.”

https://pubmed.ncbi.nlm.nih.gov/34013652/

https://onlinelibrary.wiley.com/doi/10.1111/exd.14395