The Quebec Cannabis Registry: Investigating the Safety and Effectiveness of Medical Cannabis

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“Objective: To investigate the safety and effectiveness of medical cannabis (MC) in the real-world clinical practice setting. 

Design: A 4-year prospective noncomparative registry of adult patients who initiated MC for a variety of indications. This paper reports on patients followed for up to 12 months, with interim visits at 3, 6, and 9 months after enrollment. 

Setting: Public or private outpatient clinics certified to authorize MC in the province of Quebec, Canada. 

Participants: Overall, 2991 adult (age ≥18 years) patients (mean age 51 years; 50.2% women) were enrolled between May 2015 and October 2018, with the last follow-up ending in May 2019. 

Interventions/Exposures: Cannabis products (dried, oil, or other) purchased from a Canadian licensed cannabis producer as authorized by physicians. 

Main Outcome Measures: The primary outcomes were self-reported pain severity, interference and relief (Brief Pain Inventory [BPI]), symptoms using the Revised Edmonton Symptom Assessment System (ESAS-r) and health-related quality of life dimensions (EQ-5D-5L) at baseline and each follow-up visit. The secondary outcomes were self-reported adverse events (AEs) and characteristics of cannabis treatment. 

Results: All patient-reported outcomes (BPI, ESAS-r, and EQ-5D-5L) showed a statistically significant improvement at 3 months (all p<0.01), which was maintained or further improved (for pain interference, tiredness, and well-being) over the remainder of the 12-month follow-up. Results also revealed clinically significant improvements in pain interference and tiredness, anxiety, and well-being from baseline. There were 79 AE reports (77 patients), 16 met the regulatory definition of seriousness, in which only 8 AEs were certainly or probably related to MC. 

Conclusions: MC directed by physicians appears to be safe and effective within 3 months of initiation for a variety of medical indications.”

https://pubmed.ncbi.nlm.nih.gov/36579921/

https://www.liebertpub.com/doi/10.1089/can.2022.0041

Dysmenorrhoea: Can Medicinal Cannabis Bring New Hope for a Collective Group of Women Suffering in Pain, Globally?

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“Dysmenorrhoea effects up to 90% of women of reproductive age, with medical management options including over-the-counter analgesia or hormonal contraception. There has been a recent surge in medicinal cannabis research and its analgesic properties.

This paper aims to critically investigate the current research of medicinal cannabis for pain relief and to discuss its potential application to treat dysmenorrhoea.

Relevant keywords, including medicinal cannabis, pain, cannabinoids, tetrahydrocannabinol, dysmenorrhoea, and clinical trial, have been searched in the PubMed, EMBASE, MEDLINE, Google Scholar, Cochrane Library (Wiley) databases and a clinical trial website (clinicaltrials.gov). To identify the relevant studies for this paper, 84 papers were reviewed and 20 were discarded as irrelevant.

This review critically evaluated cannabis-based medicines and their mechanism and properties in relation to pain relief. It also tabulated all clinical trials carried out investigating medicinal cannabis for pain relief and highlighted the side effects. In addition, the safety and toxicology of medicinal cannabis and barriers to use are highlighted. Two-thirds of the clinical trials summarised confirmed positive analgesic outcomes, with major side effects reported as nausea, drowsiness, and dry mouth.

In conclusion, medicinal cannabis has promising applications in the management of dysmenorrhoea. The global medical cannabis market size was valued at USD 11.0 billion in 2021 and is expected to expand at a compound annual growth rate (CAGR) of 21.06% from 2022 to 2030. This will encourage academic as well as the pharmaceutical and medical device industries to study the application of medical cannabis in unmet clinical disorders.”

https://pubmed.ncbi.nlm.nih.gov/36555842/

“Dysmenorrhoea is a medical term used to describe painful menstruation. Cannabis-based products are entering both healthcare and commercial markets with a surge in availability. With further research, cannabis-based medicines may become the norm in the management of severe or treatment-resistant dysmenorrhoea.”

https://www.mdpi.com/1422-0067/23/24/16201

Cannabis sativa CBD Extract Exhibits Synergy with Broad-Spectrum Antibiotics against Salmonella enterica subsp. Enterica serovar typhimurium

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“New generation antibiotics are needed to combat the development of resistance to antimicrobials. One of the most promising new classes of antibiotics is cannabidiol (CBD). It is a non-toxic and low-resistance chemical that can be used to treat bacterial infections.

The antibacterial activity of Cannabis sativa L. byproducts, specifically CBD, has been of growing interest in the field of novel therapeutics. As research continues to define and characterize the antibacterial activity that CBD possesses against a wide variety of bacterial species, it is important to examine potential interactions between CBD and common therapeutics such as broad-spectrum antibiotics.

In this study it is demonstrated that CBD-antibiotic (combination of CBD and antibiotic) co-therapy can effectively fight Salmonella typhimurium (S. typhimurium) via membrane integrity disruption. This research serves to examine the potential synergy between CBD and three broad-spectrum antibiotics (ampicillin, kanamycin, and polymyxin B) for potential CBD-antibiotic co-therapy. In this study, it is revealed that S. typhimurium growth is inhibited at very low dosages of CBD-antibiotic.

This interesting finding demonstrates that CBD and CBD-antibiotic co-therapies are viable novel alternatives to combating S. typhimurium.”

https://pubmed.ncbi.nlm.nih.gov/36557613/

“The decrease in antibiotic development over the 21st century has exacerbated the need for new antibacterial agents as well as new methodologies designed to retain the efficacy of current antibiotics. CBD extract from C. sativa has been presented as a promising antibacterial agent with in vitro efficacy against several relevant bacterial pathogens including Staphylococcus aureusStreptococcus pneumoniaeSalmonella spp. Clostridium difficileNeisseria spp., Moraxella catarrhalis, and Legionella pneumophila. This antibacterial activity achieved through membrane disruption of both Gram-positive and Gram-negative bacterial species presents CBD as a unique and particularly effective class of antibacterial agents.”

https://www.mdpi.com/2076-2607/10/12/2360

Anti-Bacterial Effect of Cannabidiol against the Cariogenic Streptococcus mutans Bacterium: An In Vitro Study

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“Dental caries is caused by biofilm-forming acidogenic bacteria, especially Streptococcus mutans, and is still one of the most prevalent human bacterial diseases. The potential use of cannabidiol (CBD) in anti-bacterial therapies has recently emerged.

Here we have studied the anti-bacterial and anti-biofilm activity of CBD against S. mutans. We measured minimum inhibitory concentration (MIC) and minimum biofilm inhibitory concentration (MBIC). The bacterial growth and changes in pH values were measured in a kinetic study. The biofilm biomass was assessed by Crystal Violet staining and 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) metabolic assay. Spinning Disk Confocal Microscopy (SDCM) was used to assess biofilm structure, bacterial viability and extracellular polysaccharide (EPS) production.

CBD inhibited S. mutans planktonic growth and biofilm formation in a dose-dependent manner, with similar MIC and MBIC values (5 µg/mL). CBD prevented the bacteria-mediated reduction in pH values that correlated with bacterial growth inhibition. SDCM showed a decrease of 50-fold in live bacteria and EPS production. CBD significantly reduced the viability of preformed biofilms at 7.5 µg/mL with an 80 ± 3.1% reduction of metabolic activity. At concentrations above 20 µg/mL, there was almost no bacterial recovery in the CBD-treated preformed biofilms even 48 h after drug withdrawal.

Notably, precoating of the culture plate surfaces with CBD prior to incubation with bacteria inhibited biofilm development. Additionally, CBD was found to induce membrane hyperpolarization in S. mutans. Thus, CBD affects multiple processes in S. mutans including its cariogenic properties.

In conclusion, we show that CBD has a strong inhibitory effect against cariogenic bacteria, suggesting that it is a potential drug adjuvant for reducing oral pathogenic bacterial load as well as protecting against dental caries.”

https://pubmed.ncbi.nlm.nih.gov/36555519/

“We have shown that the mode of action of CBD against S. mutans is multifactorial and attributed to: inhibition of bacterial growth and subsequently hindrance of biofilm formation, diminished biofilm metabolic activity and prevention of bacterial recovery within the biofilms following CBD treatment. Some of these effects can be attributed to the membrane hyperpolarization caused by CBD. The combined anti-bacterial and anti-metabolic effects of CBD contribute to the prevention in pH drop with implications for being a potential adjuvant drug in protecting against dental caries.”

https://www.mdpi.com/1422-0067/23/24/15878

Phytocannabinoids Act Synergistically with Non-Steroidal Anti-Inflammatory Drugs Reducing Inflammation in 2D and 3D In Vitro Models

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“Lung inflammation is associated with elevated pro-inflammatory cytokines and chemokines. Treatment with FCBD:std (standard mix of cannabidiol [CBD], cannabigerol [CBG] and tetrahydrocannabivarin [THCV]) leads to a marked reduction in the inflammation of alveolar epithelial cells, but not in macrophages.

In the present study, the combined anti-inflammatory effect of FCBD:std with two corticosteroids (dexamethasone and budesonide) and two non-steroidal anti-inflammatory drugs (NSAID; ibuprofen and diclofenac), was examined. Enzyme-linked immunosorbent assay (ELISA) was used to determine protein levels. Gene expression was determined by quantitative real-time PCR. Inhibition of cyclo-oxygenase (COX) activity was determined in vitro.

FCBD:std and diclofenac act synergistically, reducing IL-8 levels in macrophages and lung epithelial cells. FCBD:std plus diclofenac also reduced IL-6IL-8 and CCL2 expression levels in co-cultures of macrophages and lung epithelial cells, in 2D and 3D models. Treatment by FCBD:std and/or NSAID reduced COX-1 and COX-2 gene expression but not their enzymatic activity. FCBD:std and diclofenac exhibit synergistic anti-inflammatory effects on macrophages and lung epithelial cells, yet this combined activity needs to be examined in pre-clinical studies and clinical trials.”

https://pubmed.ncbi.nlm.nih.gov/36559009/

“We have shown that FCBD:std and diclofenac have synergistic anti-inflammatory effects on macrophages and lung epithelial cells, which involve the reduction of COX and CCL2 gene expression and IL levels. FCBD:std, when combined with diclofenac, can have considerably increased anti-inflammatory activity by several fold, suggesting that in an effective cannabis-diclofenac combined treatment, the level of NSAIDs may be reduced without compromising anti-inflammatory effectivity.”

https://www.mdpi.com/1424-8247/15/12/1559

Cannabinoid Compounds as a Pharmacotherapeutic Option for the Treatment of Non-Cancer Skin Diseases

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“The endocannabinoid system has been shown to be involved in various skin functions, such as melanogenesis and the maintenance of redox balance in skin cells exposed to UV radiation, as well as barrier functions, sebaceous gland activity, wound healing and the skin’s immune response.

In addition to the potential use of cannabinoids in the treatment and prevention of skin cancer, cannabinoid compounds and derivatives are of interest as potential systemic and topical applications for the treatment of various inflammatory, fibrotic and pruritic skin conditions. In this context, cannabinoid compounds have been successfully tested as a therapeutic option for the treatment of androgenetic alopecia, atopic and seborrhoeic dermatitis, dermatomyositis, asteatotic and atopic eczema, uraemic pruritis, scalp psoriasis, systemic sclerosis and venous leg ulcers. This review provides an insight into the current literature on cannabinoid compounds as potential medicines for the treatment of skin diseases.”

https://pubmed.ncbi.nlm.nih.gov/36552866/

“Based on the current publications, it can be summarised that cannabinoid compounds have great potential in the treatment of skin diseases, both as topical applications and as systemic medications.”

https://www.mdpi.com/2073-4409/11/24/4102

Cannabidiol and Beta-Caryophyllene in Combination: A Therapeutic Functional Interaction

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“Cannabis contains over 500 distinct compounds, which include cannabinoids, terpenoids, and flavonoids. However, very few of these compounds have been studied for their beneficial effects. There is an emerging concept that the constituents of the cannabis plant may work in concert to achieve better therapeutic benefits. This study is aimed at determining if the combination of a minor cannabinoid (cannabidiol, CBD) and a terpene (beta-caryophyllene, BCP) works in concert and if this has any therapeutic value. We used an inflammatory pain model (formalin) in mice to test for any functionality of CBD and BCP in combination. First, we determined the analgesic effect of CBD and BCP individually by establishing dose-response studies. Second, we tested the analgesic effect of fixed-ratio combinations and monitored any adverse effects. Finally, we determined the effect of this combination on inflammation. The combination of CBD and BCP produces a synergistic analgesic effect. This effect was without the cannabinoid receptor-1 side effects. The analgesic effect of CBD and BCP in combination involves an inflammatory mechanism. The combination of these two constituents of the cannabis plant, CBD and BCP, works in concert to produce a therapeutic effect with safety profiles through an inflammatory mechanism.”

https://pubmed.ncbi.nlm.nih.gov/36555111/

“In summary, the present data support the concept that cannabinoids and terpenes work synergistically with therapeutical value. In particular, the CBD and BCP in combination produce a synergistic analgesic effect without CB1-associated side effects. Finally, scientific investigation of the interactive effects of CBD and BCP on a therapeutic target has not been undertaken. Therefore, our present data set the stage for future studies on the therapeutic value of this combination in other diseases and testing other terpenes in combination with other cannabinoids or terpenes.”

https://www.mdpi.com/1422-0067/23/24/15470

Inhibiting Human and Leishmania Arginases Using Cannabis sativa as a Potential Therapy for Cutaneous Leishmaniasis: A Molecular Docking Study

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“Cutaneous leishmaniasis (CL), a vector-borne parasitic disease caused by the Leishmania protozoan, is a serious public health problem in Morocco. The treatment of this disease is still based on pentavalent antimonials as the primary therapy, but these have associated side effects. Thus, the development of effective, risk-free alternative therapeutics based on natural compounds against leishmaniasis is urgent. Arginase, the key enzyme in the polyamine biosynthetic pathway, plays a critical role in leishmaniasis outcome and has emerged as a potential therapeutic target.

The objective of this study was to test Cannabis sativa‘s phytochemical components (cannabinoids and terpenoids) through molecular docking against Leishmania and human arginase enzymes.

Our results showed that delta-9-tetrahydrocannabinol (THC) possessed the best binding energies of -6.02 and -6.35 kcal/mol with active sites of Leishmania and human arginases, respectively. Delta-9-THC interacted with Leishmania arginase through various amino acids including His139 and His 154 and linked to human arginase via His 126. In addition to delta-9-THC, caryophyllene oxide and cannabidiol (CBD) also showed a good inhibition of Leishmania and human arginases, respectively.

Overall, the studied components were found to inhibit both arginases active sites via hydrogen bonds and hydrophobic interactions. These components may serve as therapeutic agents or in co-administrated therapy for leishmaniasis.”

https://pubmed.ncbi.nlm.nih.gov/36548655/

“Since CL is still a public health problem in low-income and developing countries, the discovery of an efficient, less toxic, and accessible therapy is a necessity. The present in silico study was the first to investigate C. sativa’s selected constituents as selective inhibitory agents for parasitic as well as host arginases, which play an important role in this parasitic infection pathology. Interestingly, THC showed a great inhibitory potential for both species’ enzymes and will allow a better control of leishmaniasis.”

https://www.mdpi.com/2414-6366/7/12/400

Cannabis sativa L. alleviates loperamide-induced constipation by modulating the composition of gut microbiota in mice

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“MaZiRenWan (MZRW) is the most frequently used Traditional Chinese Medicine formula to treat chronic constipation, Cannabis sativa L. is regarded as a monarch drug in MZRW. However, the targets of Cannabis sativa L. that enhance colonic motility and improve constipation symptoms remain unknown.

This study was designed to investigate the laxative effect and underlying mechanism of the water extract of Cannabis sativa L. (WECSL) using a loperamide-induced constipation mouse model.

We found that WECSL treatment significantly improved intestinal motility and water-electrolyte metabolism, decreased inflammatory responses, prevented gut barrier damage, and relieved anxiety and depression in constipated mice. WECSL also structurally remodeled the composition of the gut microbiota and altered the abundance of bacteria related to inflammation, specifically Butyricicoccus and Parasutterella. Moreover, WECSL failed to relieve constipation symptoms following intestinal flora depletion, indicating that WECSL alleviates constipation symptoms depending on the gut microbiota.

Our research provides a basis for WECSL to be further investigated in the treatment of constipation from the perspective of modern medicine.”

https://pubmed.ncbi.nlm.nih.gov/36532754/

“In conclusion, this study demonstrated that WECSL can improve constipation symptoms, reduce anxiety and depression behaviors, and inhibit intestinal inflammation. WECSL also structurally remodeled the composition of the gut microbiota, altering the abundance of bacteria related to inflammation.

Our research provides a basis for WECSL to be further investigated in the treatment of constipation from the perspective of modern medicine. Constipation may be prevented and improved by targeting these possible gut bacteria.”

https://www.frontiersin.org/articles/10.3389/fphar.2022.1033069/full


Topical Cannabidiol in the Treatment of Digital Ulcers in Patients with Scleroderma: Comparative Analysis and Literature Review

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“Objective: To explore the effect of topical cannabidiol (CBD) in treating digital ulcers in patients with systemic sclerosis (SSc).

Methods: In total, 45 patients with SSc who had digital ulcers were consecutively enrolled between January 2019 and December 2019. Of the participants, 25 were treated with CBD during surgical debridement and 20 were treated with standard local therapy. A numeric rating scale for pain and Health Assessment Questionnaire Disability Index were administered at the baseline and at the end of treatment.

Results: Local treatment with CBD was significantly associated with lower pain scores, higher health assessment scores, and an increase in participants’ total hours of sleep. Patients in the control group more frequently required additional analgesic therapy.

Conclusions: Topical CBD may be a valuable tool to treat pain related to digital ulcers in patients with SSc.”

https://pubmed.ncbi.nlm.nih.gov/36537770/

“Topical administration of CBD is a safe, effective, noninvasive tool that is associated with improved wound-related pain, DU healing, and QoL of patients with SSc.”

https://journals.lww.com/aswcjournal/Fulltext/2023/01000/Topical_Cannabidiol_in_the_Treatment_of_Digital.4.aspx