“Bones and Joints” The Role of Cannabidiol (CBD) in Musculoskeletal Health

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“Cannabis has a rich history as a therapeutic tool with wide ranging applications.

The efficacy of cannabidiol (CBD), the non-psychoactive component of cannabis, has been well demonstrated for pain management. Further, recent orthopedic studies have demonstrated positive effects of CBD on wound healing, inflammation, bone marrow density, and fracture healing.

Despite the growing interest in CBD, there is a paucity of research on its impact on fracture risk and bone density in human clinical trials and the existing literature has significant limitations. As the rate of cannabis consumption increases, further research is essential to delineate the therapeutic qualities of CBD and its long-term effects on fracture healing and bone metabolism in order to optimize patient outcomes.”

https://pubmed.ncbi.nlm.nih.gov/36821737/

“Cannabidiol, a Major Non-Psychotropic Cannabis Constituent Enhances Fracture Healing and Stimulates Lysyl Hydroxylase Activity in Osteoblasts”

https://pubmed.ncbi.nlm.nih.gov/25801536/

The Endocannabinoid System and Physical Exercise

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“The endocannabinoid system (ECS) is involved in various processes, including brain plasticity, learning and memory, neuronal development, nociception, inflammation, appetite regulation, digestion, metabolism, energy balance, motility, and regulation of stress and emotions.

Physical exercise (PE) is considered a valuable non-pharmacological therapy that is an immediately available and cost-effective method with a lot of health benefits, one of them being the activation of the endogenous cannabinoids.

Endocannabinoids (eCBs) are generated as a response to high-intensity activities and can act as short-term circuit breakers, generating antinociceptive responses for a short and variable period of time.

A runner’s high is an ephemeral feeling some sport practitioners experience during endurance activities, such as running. The release of eCBs during sustained physical exercise appears to be involved in triggering this phenomenon.

The last decades have been characterized by an increased interest in this emotional state induced by exercise, as it is believed to alleviate pain, induce mild sedation, increase euphoric levels, and have anxiolytic effects.

This review provides information about the current state of knowledge about endocannabinoids and physical effort and also an overview of the studies published in the specialized literature about this subject.”

https://pubmed.ncbi.nlm.nih.gov/36768332/

“PE is considered a valuable non-pharmacological therapy that is an immediately available and cost-effective method with many health benefits, one of them being the activation of endogenous cannabinoids to reduce stress and anxiety and improve wellness.”

https://www.mdpi.com/1422-0067/24/3/1989

“Exercise activates the endocannabinoid system”

https://pubmed.ncbi.nlm.nih.gov/14625449/

Efficacy and safety of topical 0.1% cannabidiol for managing recurrent aphthous ulcers: a randomized controlled trial

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BMC Complementary Medicine and Therapies | Home page

“Background: Although topical steroids constitute the first-line therapy for recurrent aphthous ulcers (RAUs), their long-term use often leads to candidiasis. Although cannabidiol (CBD) can be an alternative for pharmacologically managing RAUs due to its analgesic and anti-inflammatory in vivo effects, there is a lack of clinical and safety trials concerning its use. The aim of this study was to evaluate the clinical safety and efficacy of topical 0.1% CBD for managing RAU.

Methods: A CBD patch test was performed on 100 healthy subjects. CBD was applied on the normal oral mucosa of 50 healthy subjects 3 times/day for 7 days. Oral examination, vital signs, and blood tests were performed pre- and post-CBD use. Another 69 RAU subjects randomly received one of three topical interventions: 0.1% CBD, 0.1% triamcinolone acetonide (TA), or placebo. These were applied on the ulcers 3 times/day for 7 days. The ulcer and erythematous size were measured on day 0, 2, 5, and 7. Pain ratings were recorded daily. The subjects rated their satisfaction with the intervention and completed a quality-of-life questionnaire (OHIP-14).

Results: None of the subjects exhibited allergic reactions or side effects. Their vital signs and blood parameters were stable before and after the 7-day CBD intervention. CBD and TA significantly reduced ulcer size more than placebo at all time points. The erythematous size reduction was higher in the CBD intervention than the placebo on day 2, while TA reduced the erythematous size at all time points. The pain score in the CBD group was lower compared with placebo on day 5, whereas TA reduced pain more than placebo on day 4, 5, and 7. The subjects receiving CBD reported higher satisfaction than placebo. However, the OHIP-14 scores were comparable among the interventions.

Conclusions: Topical 0.1% CBD reduced ulcer size and accelerated ulcer healing without side effects. CBD exerted anti-inflammatory effects in the early stage and an analgesic effect in the late RAU stage. Thus, topical 0.1% CBD might be more appropriate for RAU patients who decline to take topical steroids, except for cases where CBD is contraindicated.”

https://pubmed.ncbi.nlm.nih.gov/36803360/

“This clinical study demonstrated that topical 0.1% CBD reduced ulcer size and accelerated ulcer healing without any reported local (signs of allergic and anaphylactic reactions) or systemic (vital sign and blood test alteration) side effects. Furthermore, in the RCT, topical CBD exerted an anti-inflammatory effect by reducing the erythematous border size in the early stage and decreased pain intensity in the late stage of RAU. Thus, CBD may be appropriate for RAU patients who choose not to take topical steroids, except for cases where CBD is contraindicated, such as being allergic to CBD, a history of drug or alcohol addiction, and a history of mood disorders.”

https://bmccomplementmedtherapies.biomedcentral.com/articles/10.1186/s12906-023-03886-0

Management of Chronic Anal Fissure with a Novel Topical Hemp-Herbal-Based Ointment: A Pilot Study

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“Introduction: Anal fissure (AF) is a common anorectal disease. Although several pharmacological treatments are available, many patients still require surgical interventions. In this study, we aimed to evaluate the efficacy of an ointment based on a multifunctional blend of herbal ingredients including hemp (ProctoFiz) for chronic AF.

Methods: A single-arm, questionnaire-based prospective study was conducted in a large tertiary center to evaluate the outcomes of patients suffering from chronic AF treated with topical ProctoFiz.

Results: Ninety-two patients were included in the study, 54 (58.7%) were females with a median age of 39 (range 17-78). 32 patients (34.7%) suffered from recurrent AF before enrolling in the study, and 5 patients (5.4%) underwent previous surgical interventions for AF. Three patients (3.2%) were lost to follow-up, leaving 89 patients for analysis. Eighty patients (89.9%) reported significant improvement of symptoms after 1 week using ProctoFiz, and 79 patients reported continued improvement after 1 month of treatment. The mean pain Visual Analog Score (VAS) declined by 6.6 points (8.9 vs. 2.3; 95% CI: 7.20 to -5.99, p < 0.0001) following 1 week of treatment, with continuous improvement to a mean of 0.64 after 1 month. Negative impact on quality of life significantly decreased from a mean of 8.8 to 0.38 following a month of treatment (p < 0.0001), with significant reduction in the number of patients suffering from bleeding following bowel movements (64.1-2.5%; p = 0.0001).

Conclusion: Hemp-based topical treatment of AF is feasible and significantly improves AF-correlated symptoms.”

https://pubmed.ncbi.nlm.nih.gov/36814684/

Endocannabinoids are potential inhibitors of glioblastoma multiforme proliferation

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Journal of Integrative Medicine

“Globally, it is evident that glioblastoma multiforme (GBM) is an aggressive malignant cancer with a high mortality rate and no effective treatment options. Glioblastoma is classified as the stage-four progression of a glioma tumor, and its diagnosis results in a shortened life expectancy. Treatment options for GBM include chemotherapy, immunotherapy, surgical intervention, and conventional pharmacotherapy; however, at best, they extend the patient’s life by a maximum of 5 years. GBMs are considered incurable due to their high recurrence rate, despite various aggressive therapeutic approaches which can have many serious adverse effects.

Ceramides, classified as endocannabinoids, offer a promising novel therapeutic approach for GBM. Endocannabinoids may enhance the apoptosis of GBM cells but have no effect on normal healthy neural cells. Cannabinoids promote atypical protein kinase C, deactivate fatty acid amide hydrolase enzymes, and activate transient receptor potential vanilloid 1 (TRPV1) and TRPV2 to induce pro-apoptotic signaling pathways without increasing endogenous cannabinoids. In previous in vivo studies, endocannabinoids, chemically classified as amide formations of oleic and palmitic acids, have been shown to increase the pro-apoptotic activity of human cancer cells and inhibit cell migration and angiogenesis.

This review focuses on the biological synthesis and pharmacology of endogenous cannabinoids for the enhancement of cancer cell apoptosis, which have potential as a novel therapy for GBM.”

https://pubmed.ncbi.nlm.nih.gov/36805391/

“As discussed above, endocannabinoids could prove to be a viable alternative treatment for GBM.”

https://www.sciencedirect.com/science/article/abs/pii/S2095496423000055?via%3Dihub

Delving into The Death Signaling Pathway of Hemp Oil and Gamma Radiation in Solid Tumor Bearing Mice

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New publication in Canadian Journal of Physiology and Pharmacology – Institute of Molecular Biomedicine

“Many studies reported the diverse therapeutic potential of essential oils, including cancer prevention and treatment. Many mechanisms involved in these processes including antioxidant, antimutagenic and antiproliferative effects, or by enhancing immune function and surveillance, inducing enzymes, and enhancing detoxification, and modulating multidrug resistance.

Hemp oil, obtained from Cannabis sativa L. seeds, is known for its nutritive, health-enhancing properties and bioactivity.

Adult female Swiss albino mice were injected with viable Ehrlich ascites carcinoma cells (2.5 x 106 cells/mouse) then administered with hemp oil (20 mg/kg) daily for 10 consecutive days pre and post exposure to 6Gy whole body gamma radiation. Hemp oil induced a significant increase in Beclin1, VMP1, LC3, cytochrome c and Bax. Otherwise, the oil showed a significant decrease in Bcl2 and P13k either alone or in combination with ɤ-radiation.

Finally this study revealed the role of hemp oil in inducing two cell death types ;autophagy and apoptosis as it may be applied as an adjuvant in cancer treatment.”

https://pubmed.ncbi.nlm.nih.gov/36812473/

https://cdnsciencepub.com/doi/10.1139/cjpp-2022-0319

A novel mechanism of cannabidiol in suppressing ovarian cancer through LAIR-1 mediated mitochondrial dysfunction and apoptosis

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“Cannabidiol (CBD) is a nonpsychoactive cannabinoid compound. It has been shown that CBD can inhibit the proliferation of ovarian cancer cells, but the underlying specific mechanism is unclear.

We previously presented the first evidence for the expression of leukocyte-associated immunoglobulin-like receptor 1 (LAIR-1), a member of the immunosuppressive receptor family, in ovarian cancer cells. In the present study, we investigated the mechanism by which CBD inhibits the growth of SKOV3 and CAOV3 ovarian cancer cells, and we sought to understand the concurrent role of LAIR-1.

In addition to inducing ovarian cancer cell cycle arrest and promoting cell apoptosis, CBD treatment significantly affected the expression of LAIR-1 and inhibited the PI3K/AKT/mTOR signaling axis and mitochondrial respiration in ovarian cancer cells. These changes were accompanied by an increase in ROS, loss of mitochondrial membrane potential, and suppression of mitochondrial respiration and aerobic glycolysis, thereby inducing abnormal or disturbed metabolism and reducing ATP production. A combined treatment with N-acetyl-l-cysteine and CBD indicated that a reduction in ROS production would restore PI3K/AKT/mTOR pathway signaling and ovarian cancer cell proliferation. We subsequently confirmed that the inhibitory effect of CBD on the PI3K/AKT/mTOR signal axis and mitochondrial bioenergy metabolism was attenuated by knockdown of LAIR-1. Our animal studies further support the in vivo anti-tumor activity of CBD and suggest its mechanism of action.

In summary, the present findings confirm that CBD inhibits ovarian cancer cell growth by disrupting the LAIR-1-mediated interference with mitochondrial bioenergy metabolism and the PI3K/AKT/mTOR pathway. These results provide a new experimental basis for research into ovarian cancer treatment based on targeting LAIR-1 with CBD.”

https://pubmed.ncbi.nlm.nih.gov/36810933/

https://onlinelibrary.wiley.com/doi/10.1002/tox.23752

Patient Reported Outcomes Using Medical Cannabis for Managing Pain in Charcot-Marie-Tooth Disease

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“Objective: Chronic pain is a major problem for patients with Charcot-Marie-Tooth (CMT) disease. This exploratory study examined patient reported efficacy of medical cannabis for pain management in this population. 

Methods: Participants (N = 56; 71.4% female; Age = 48.9, SD = 14.6; 48.5% CMT1) were recruited though the Hereditary Neuropathy Foundation. The online survey contained 52 multiple choice questions about demographics, medical cannabis use, symptomology, efficacy, and adverse effects. 

Results: Nearly all (90.9%) of respondents reported experiencing pain, including all (100%) females and 72.7% of males (chi-square P < .05) with 91.7% of respondents indicating cannabis provided at least 50% pain relief. The most frequent response was an 80% reduction in pain. Moreover, 80.0% of respondents reported using less opiates, 69% noted using less sleep medication, and 50.0% reported using less anxiety/antidepressant medications. Negative side effects were noted by 23.5% of respondents. However, almost all (91.7%) of that subgroup did not have plans to stop consuming cannabis. One-third (33.9%) possessed a medical cannabis certificate. Patient perceptions of their physicians’ attitudes regarding patient medical cannabis use greatly impacted whether respondents informed their providers of their usage. 

Conclusion: The vast majority of patients with CMT reported that cannabis was effective to manage pain symptoms. These data support the need for prospective, randomized, controlled trials using standardized dosing protocols to further delineate and optimize the potential use of cannabis to treat pain related to CMT.”

https://pubmed.ncbi.nlm.nih.gov/36793224/

https://journals.sagepub.com/doi/10.1177/10499091231158388

A Retrospective Cohort Study That Examined the Impact of Cannabis Consumption on Long-Term Kidney Outcomes

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“Background: Cannabis consumption for recreational and medical use is increasing worldwide. However, the long-term effects on kidney health and disease are largely unknown. 

Materials and Methods: Post hoc analysis of cannabis use as a risk factor for kidney disease was performed using data from the Assessment, Serial Evaluation, and Subsequent Sequelae of Acute Kidney Injury (ASSESS-AKI) study that enrolled hospitalized adults with and without acute kidney injury from four U.S. centers during 2009-2015. Associations between self-reported cannabis consumption and the categorical and continuous outcomes were determined using multivariable Cox regression and linear mixed models, respectively. 

Results: Over a mean follow-up of 4.5±1.8 years, 94 participants without chronic kidney disease (CKD) (estimated glomerular filtration rate [eGFR] >60 mL/min/1.73 m2) who consumed cannabis had similar rates of annual eGFR decline versus 889 nonconsumers (mean difference=-0.02 mL/min/1.73 m2/year, p=0.9) and incident CKD (≥25% reduction in eGFR compared with the 3-month post-hospitalization measured eGFR and achieving CKD stage 3 or higher) (adjusted hazard ratio [aHR]=1.2; 95% confidence interval [CI]=0.7-2.0). Nineteen participants with CKD (eGFR <60 mL/min/1.73 m2) who consumed cannabis had more rapid eGFR decline versus 597 nonconsumers (mean difference=-1.3 mL/min/1.73 m2/year; p=0.02) that was not independently associated with an increased risk of CKD progression (≥50% reduction in eGFR compared with the 3-month post-hospitalization eGFR, reaching CKD stage 5, or receiving kidney replacement therapy) (aHR=1.6; 95% CI=0.7-3.5). Cannabis consumption was not associated with the rate of change in urine albumin to creatinine ratio (UACR) over time among those with (p=0.7) or without CKD (p=0.4). 

Conclusions: Cannabis consumption did not adversely affect the kidney function of participants without CKD but was associated with a faster annual eGFR decline among participants with CKD. Cannabis consumption was not associated with changes in UACR over time, incident CKD, or progressive CKD regardless of baseline kidney function. Additional research is needed to investigate the kidney endocannabinoid system and the impact of cannabis use on kidney disease outcomes.”

https://pubmed.ncbi.nlm.nih.gov/36791309/

https://www.liebertpub.com/doi/10.1089/can.2022.0141

Safety Assessment and Redox Status in Rats after Chronic Exposure to Cannabidiol and Cannabigerol

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Toxicology

“Cannabidiol (CBD) and cannabigerol (CBG) are the two main non-psychotropic phytocannabinoids with high application potential in drug development. Both substances are redox-active and are intensively investigated for their cytoprotective and antioxidant action in vitro. In this study, we focused on an in vivo safety evaluation and the effect of CBD and CBG on the redox status in rats in a 90-d experiment. The substances were administered orogastrically in a dose of 0.66mg synthetic CBD or 0.66mg/1.33mg CBG/kg/day. CBD produced no changes in the red or white blood count or biochemical blood parameters in comparison to the control. No deviations in the morphology or histology of the gastrointestinal tract and liver were observed. After 90 d of CBD exposure, a significant improvement in redox status was found in the blood plasma and liver. The concentration of malondialdehyde and carbonylated proteins was reduced compared to the control. In contrast to CBD, total oxidative stress was significantly increased and this was accompanied by an elevated level of malondialdehyde and carbonylated proteins in CBG-treated animals. Hepatotoxic (regressive changes) manifestations, disruption in white cell count, and alterations in the ALT activity, level of creatinine and ionized calcium were also found in CBG-treated animals. Based on liquid chromatography-mass spectrometry analysis, CBD/CBG accumulated in rat tissues (in the liver, brain, muscle, heart, kidney and skin) at a low ng level per gram. Both CBD and CBG molecular structures include a resorcinol moiety. In CBG, there is an extra dimethyloctadienyl structural pattern, which is most likely responsible for the disruption to the redox status and hepatic environment. The results are valuable to further investigation of the effects of CBD on redox status and should contribute towards opening up critical discussion on the applicability of other non-psychotropic cannabinoids.”

https://pubmed.ncbi.nlm.nih.gov/36796712/

https://www.sciencedirect.com/science/article/abs/pii/S0300483X2300046X?via%3Dihub