Cutaneous Wound Healing and the Effects of Cannabidiol

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“Cutaneous wounds, both acute and chronic, begin with loss of the integrity, and thus barrier function, of the skin. Surgery and trauma produce acute wounds. There are 22 million surgical procedures per year in the United States alone, based on data from the American College of Surgeons, resulting in a prevalence of 6.67%. Acute traumatic wounds requiring repair total 8 million per year, 2.42% or 24.2 per 1000. The cost of wound care is increasing; it approached USD 100 billion for just Medicare in 2018. This burden for wound care will continue to rise with population aging, the increase in metabolic syndrome, and more elective surgeries.

To heal a wound, an orchestrated, evolutionarily conserved, and complex series of events involving cellular and molecular agents at the local and systemic levels are necessary. The principal factors of this important function include elements from the neurological, cardiovascular, immune, nutritional, and endocrine systems.

The objectives of this review are to provide clinicians engaged in wound care and basic science researchers interested in wound healing with an updated synopsis from recent publications. We also present data from our primary investigations, testing the hypothesis that cannabidiol can alter cutaneous wound healing and documenting their effects in wild type (C57/BL6) and db/db mice (Type 2 Diabetes Mellitus, T2DM).

The focus is on the potential roles of the endocannabinoid system, cannabidiol, and the important immune-regulatory wound cytokine IL-33, a member of the IL-1 family, and connective tissue growth factor, CTGF, due to their roles in both normal and abnormal wound healing. We found an initial delay in the rate of wound closure in B6 mice with CBD, but this difference disappeared with time. CBD decreased IL-33 + cells in B6 by 70% while nearly increasing CTGF + cells in db/db mice by two folds from 18.6% to 38.8% (p < 0.05) using a dorsal wound model. We review the current literature on normal and abnormal wound healing, and document effects of CBD in B6 and db/db dorsal cutaneous wounds.

CBD may have some beneficial effects in diabetic wounds. We applied 6-mm circular punch to create standard size full-thickness dorsal wounds in B6 and db/db mice. The experimental group received CBD while the control group got only vehicle. The outcome measures were rate of wound closure, wound cells expressing IL-33 and CTGF, and ILC profiles. In B6, the initial rate of wound closure was slower but there was no delay in the time to final closure, and cells expressing IL-33 was significantly reduced. CTGF + cells were higher in db/bd wounds treated with CBD.

These data support the potential use of CBD to improve diabetic cutaneous wound healing.”

https://pubmed.ncbi.nlm.nih.gov/39000244/

“The endocannabinoid system is an elaborate, complex, and adaptive monitoring and modulating apparatus. Phytocannabinoids mimic the actions of the endogenous bioactive lipids derived from arachidonic acid and have unequivocal and very wide-ranging effects, including decreasing inflammatory responses following cutaneous injuries. While we will continue to explore, at the macroscopic level, the therapeutic clinical applications, the efforts to understand mechanistically, at the micro- and nano-levels, why and how CBD causes these observed beneficial effects are increasingly more important. Such a multi- or trans-scalar (fractal) approach allows for the targeted expansion and refinement of CBD use.”

https://www.mdpi.com/1422-0067/25/13/7137

Comparison of various doses of oral cannabidiol for treating refractory epilepsy indications: a network meta-analysis

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“Aim: To evaluate the comparative efficacy and safety of various doses of oral cannabidiol (CBD) in treating refractory epilepsy indications, thus providing more informative evidence for clinical decision-making.

Methods: A literature search of PubMed, Embase, the Cochrane library, and Web of Science (WoS) was performed to retrieve relevant randomized controlled trials (RCTs) that compared different doses of oral CBD with placebo or each other in refractory epilepsy indications. The search was limited from the inception of each database to January 3, 2023. Relative risk [RR] with a 95% confidence interval [CI] was used to express results. STATA/SE 14 was employed for network meta-analysis.

Results: Six RCTs involving 972 patients were included in the final data analysis. Network meta-analysis showed that, CBD10 (10 mg/kg/day) (RR: 1.77, 95%CI: 1.28 to 2.44), CBD20 (20 mg/kg/day) (RR: 1.91, 95%CI: 1.49 to 2.46), CBD25 (25 mg/kg/day) (RR: 1.61, 95%CI: 0.96 to 2.70), and CBD50 (50 mg/kg/day) (RR: 1.78, 95%CI: 1.07 to 2.94) were associated with higher antiseizure efficacy although the pooled result for CBD25 was only close to significant. In addition, in terms of the risk of treatment-emergent adverse events (TEAEs), the difference between different doses is not significant. However, CBD20 ranked first in terms of antiseizure efficacy, followed by CBD50, CBD10, and CBD25. For TEAEs, CBD25 ranked first, followed by CBD10, CBD50, CBD5, and CBD20.

Conclusion: For refractory indications, CBD20 may be optimal option for antiseizure efficacy; however, CBD25 may be best for TEAEs. Therefore, an appropriate dose of oral CBD should be selected based on the actual situation. Due to the limitations of eligible studies and the limited sample size, more studies are needed in the future to validate our findings.”

https://pubmed.ncbi.nlm.nih.gov/38994494/

https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2024.1243597/full

Impact of Medical Cannabis on Recovery from Playing-Related Musculoskeletal Disorders in Musicians: An Observational Cohort Study

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“Introduction: Playing-related musculoskeletal disorders (PRMDs) are musculoskeletal symptoms that interfere with the ability to play at the level a musician is accustomed to. Musicians have an 84% lifetime prevalence of PRMD. Many types of analgesia are inappropriate for this population due to their risks, but cannabidiol (CBD) has been shown to have anti-inflammatory properties and can reduce the perception of pain. Medical cannabis has also been shown to be safer than other analgesia in terms of serious adverse events. This study explores the impact of medical cannabis for PRMD on perceptions of pain and mental health outcomes.

Methods: Participants (n = 204) completed questionnaires at baseline and six months: the Musculoskeletal Pain Intensity and Interference Questionnaire for Musicians (MPIIQM) and Depression, Anxiety and Stress Scale (DASS-21). Participants self-selected their group: non-cannabis users (n = 42), new medical cannabis users (n = 61), and long-term medical cannabis users (n = 101). Data were analyzed using paired t-tests for within-group and ANOVA for between-group differences.

Results: At six months, there was no difference (p = 0.579) in cannabidiol dose between new (24.87 ± 12.86 mg) and long-term users (21.48 ± 12.50 mg). There was a difference in tetrahydrocannabinol (THC) dose (p = 0.003) between new (3.74 ± 4.22 mg) and long-term users (4.41 ± 5.18 mg). At six months, new cannabis users had a significant reduction in pain intensity as measured by The Musculoskeletal Pain Intensity and Interference Questionnaire for Musicians (MPIIQM40) (p = 0.002). Non-users (p = 0.035), new users (p = 0.002), and long-term cannabis users (p = 0.009) all had significant reductions in pain interference (MPIIQM50) at six months. At six months, non-cannabis (p = 0.022) and long-term cannabis users (p = 0.001) had an improvement in DASS-21. The change in pain intensity was the only difference between groups, F(2, 201) = 3.845, p = 0.023. This difference was between long-term (0.83 ± 0.79) and new users (-2.61 ± 7.15). No serious adverse events occurred, and a minority experienced tiredness, cough, and dry mouth.

Discussion/conclusions: This practice-based evidence demonstrated that the multidimensional approach to care provided by the Musicians’ Clinics of Canada benefited all groups at six months. Medical cannabis significantly reduced pain intensity in new users of medical cannabis with PRMD, and all groups saw improvements in pain interference. In keeping with prior studies, medical cannabis seems to be effective at reducing perceptions of pain, including for PRMD. CBD/THC dosing was within guideline recommendations, and no patients experienced any serious adverse events. Limitations include multiple factors impacting patients’ decisions to opt in or out of medical cannabis. These include cost, comorbidities, and disease chronicity. In conclusion, medical cannabis reduces pain intensity in new users, and when combined with a multidimensional approach to care, patients with PRMD can see improvements in pain as well as mental wellbeing.”

https://pubmed.ncbi.nlm.nih.gov/38998869/

“In conclusion, within our study population over a six-month period, medical cannabis proved to be a safe and potentially beneficial treatment option for musicians with PRMD, with those using medical cannabis for the first time seeing a statistically significant reduction in pain intensity. All patient groups experienced an improvement in some domains of pain experience or mental wellbeing, likely due to the multidimensional model of care. Many patient concerns about medical cannabis include adverse drug effects, addiction, tolerance, losing control, or unusual behavior [21], but hopefully this paper will add further evidence to the literature to help patients make informed decisions in keeping with their preferences and values. A key conclusion from this study is the importance of shared decision making to ensure that patient values, as well as individual symptoms and situations, are considered. N-of-1 trials may be used to further explore optimal individualized treatment plans [49], as well as randomized-controlled trials to build the evidence base for musicians with PRMD in general.”

https://www.mdpi.com/2227-9032/12/13/1335

Acute effects of cannabigerol on anxiety, stress, and mood: a double-blind, placebo-controlled, crossover, field trial

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“Cannabigerol (CBG) is a phytocannabinoid increasing in popularity, with preclinical research indicating it has anxiolytic and antidepressant effects. However, there are no published clinical trials to corroborate these findings in humans.

The primary objective of this study was to examine acute effects of CBG on anxiety, stress, and mood. Secondary objectives were to examine whether CBG produces subjective drug effects or motor and cognitive impairments. A double-blind, placebo-controlled cross-over field trial was conducted with 34 healthy adult participants. Participants completed two sessions (with a one-week washout period) via Zoom. In each, they provided ratings of anxiety, stress, mood, and subjective drug effects prior to double-blind administration of 20 mg hemp-derived CBG or placebo tincture (T0). These ratings were collected again after participants ingested the product and completed an online survey (T1), the Trier Social Stress Test (T2), a verbal memory test and the DRUID impairment app (T3).

Relative to placebo, there was a significant main effect of CBG on overall reductions in anxiety as well as reductions in stress at T1. CBG also enhanced verbal memory relative to placebo. There was no evidence of subjective drug effects or impairment. CBG may represent a novel option to reduce stress and anxiety in healthy adults.”

https://pubmed.ncbi.nlm.nih.gov/39003387/

“In conclusion, results of this double-blind, placebo-controlled, cross-over field trial indicate that 20 mg of hemp-derived CBG reduces subjective ratings of anxiety and stress in healthy cannabis-using adults in the absence of motor or cognitive impairment, intoxication, or other subjective drug effects (e.g., heart palpitations, dry mouth).”

https://www.nature.com/articles/s41598-024-66879-0

Canniprene B, a new prenylated dihydrostilbene with cytotoxic activities from the leaves of Cannabis sativa

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“A new, canniprene B (4), along with five known (13 and 56) dihydrostilbenes were isolated from the leaves of Cannabis sativa collected at CSIR – IIIM, Jammu, India. Structures of all isolated compounds were elucidated by spectroscopic data analysis, including 1D and 2D NMR, and HR-ESI-MS. Canniprene B is a new prenylated dihydrostilbenes, a positional isomer of the known compound canniprene (5). The cytotoxic activities of these compounds (16) were evaluated using the SRB assay against a panel of five human cancer cell lines. Notably, canniprene B (4) exhibited varying levels of cytotoxicity with IC50 values ranging from 2.5 to 33.52 μM, demonstrating the most potent activity against pancreatic cancer cells.”

https://pubmed.ncbi.nlm.nih.gov/38989798/

https://www.tandfonline.com/doi/full/10.1080/14786419.2024.2376348


NHS-Reimbursed Cannabis Flowers for Cancer Palliative Care and the Management of Chemotherapy-Induced Nausea and Vomiting: An Autobiographical Case Report

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“Chemotherapy-induced nausea and vomiting (CINV) is a debilitating side effect of cancer treatment, affecting many patients. Cannabinoid agonists, such as nabilone and Δ9-tetrahydrocannabinol (THC), the main psychoactive component of Cannabis sativa L., have shown efficacy as antiemetics.

Here, we report the case of Michael Roberts (MR), who we believe is the first British patient reimbursed by the National Health Service (NHS) England for the cost of medicinal cannabis flowers to manage CINV. Medical data were obtained from NHS records and individual funding request (IFR) forms. Patient-reported outcome measures (PROMs) were collected using validated questionnaires as part of the standard of care at the specialized private clinics where the prescription of medicinal cannabis was initiated. The patient presented with rectosigmoid adenocarcinoma with lung metastases. He received FOLFIRI (folinic acid, fluorouracil, and irinotecan) chemotherapy and underwent an emergency Hartmann’s procedure with subsequent second-line FOLFOX (folinic acid, fluorouracil, and oxaliplatin) chemotherapy and lung ablation. MR reported severe nausea and vomiting associated with the initial FOLFIRI treatment. Antiemetics metoclopramide and aprepitant demonstrated moderated efficacy. Antiemetics ondansetron, levomepromazine, and nabilone were associated with intolerable side effects.

Inhalation of THC-predominant cannabis flowers in association with standard medication improved CINV, anxiety, sleep quality, appetite, overall mood, and quality of life.

Our results add to the available evidence suggesting that medicinal cannabis flowers may offer valuable support in cancer palliative care integrated with standard-of-care oncology treatment. The successful individual funding request in this case demonstrates a pathway for other patients to gain access to these treatments, advocating for broader awareness and integration of cannabis-based medicinal products in national healthcare services.”

https://pubmed.ncbi.nlm.nih.gov/38975420/

“This case report highlights the potential of THC-predominant cannabis flowers in the management of CINV in a cancer patient, marking a significant step in palliative cancer care. Michael Roberts, who we believe is the first NHS patient reimbursed for medicinal cannabis flowers, experienced substantial relief from CINV, alongside improvements in pain, anxiety, sleep, appetite, and overall quality of life. His case underscores the therapeutic benefits of controlled inhalation of cannabis flowers, particularly in patients unresponsive to conventional antiemetics. This report brings further attention to the challenges faced by patients in accessing CBMPs within the NHS, despite their legalization and acknowledged potential in symptom management. The successful individual funding request in this case demonstrates a pathway for other patients to gain access to these treatments, advocating for broader awareness and integration of CBMPs in national healthcare systems.”

https://www.cureus.com/articles/166147-nhs-reimbursed-cannabis-flowers-for-cancer-palliative-care-and-the-management-of-chemotherapy-induced-nausea-and-vomiting-an-autobiographical-case-report#!/

Efficacy of cannabis-based medicine in the treatment of Tourette syndrome: a systematic review and meta-analysis

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“Background: Tourette syndrome (TS) is a neurodevelopmental disorder characterized by motor and phonic tics. It is a condition that affects between 0.3% and 0.7% of children, and its pathophysiology remains largely elusive. TS is associated with structural and functional alterations in corticostriatal circuits and neurochemical imbalances. Even though TS is currently incurable, there are established treatment options available, including behavioral therapy and neuroleptics. The use of cannabis-based medicine for tic management is an emerging therapeutic strategy, although its efficacy is still under investigation. It is hypothesized to interact with the endogenous cannabinoid system, but further research is required to ascertain its safety and effectiveness in TS.

Aim: In our systematic review and meta-analysis, we aim to assess the effectiveness of cannabis-based medicine in the treatment of TS.

Methods: We searched PubMed, Cochrane, Scopus, and Web of Sciences until February 2024. We included clinical trials and cohort studies investigating the efficacy of cannabis-based medicine in the treatment of TS. Data extraction focused on baseline characteristics of the included studies and efficacy outcomes, including scores on the Yale Global Tic Severity Scale (YGTSS), Premonitory Urge for Tics Scale (PUTS), and Yale-Brown Obsessive Compulsive Scale (Y-BOCS). We conducted the meta-analysis using Review Manager version 5.4. software. We compared the measurements before and after drug intake using mean difference (MD) and 95% confidence interval (CI).

Results: In total, 357 articles were identified for screening, with nine studies included in the systematic review and 3 in the meta-analysis. These studies involved 401 adult patients with TS treated with cannabis. YGTSS revealed a significant reduction in total scores (MD = -23.71, 95% CI [-43.86 to -3.55], P = 0.02), PUTS revealed a significant decrease in scores (MD = -5.36, 95% CI [-8.46 to -2.27], P = 0.0007), and Y-BOCS revealed no significant difference in score reduction (MD = -6.22, 95% CI [-12.68 to 0.23], P = 0.06).

Conclusion: The current study indicates promising and potentially effective outcomes with the use of cannabis-based medicine in mitigating the severity of tics and premonitory urges. However, there is a need for larger, placebo-controlled studies with more representative samples to validate these findings.”

https://pubmed.ncbi.nlm.nih.gov/38985199/

https://link.springer.com/article/10.1007/s00228-024-03710-9

Cannabidiol effectively prevents oxidative stress and stabilizes hypoxia-inducible factor-1 alpha (HIF-1α) in an animal model of global hypoxia

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“Cannabidiol (CBD) is a non-psychotomimetic phytocannabinoid derived from Cannabis sativa. It has therapeutic effects in different paradigms of brain injury, acting as a neuroprotectant.

As oxidative stress is a primary risk factor for brain damage after neonatal hypoxia, we tested the effect of CBD on oxidative status and non-protein-bound iron accumulation in the immature brain after hypoxia. Moreover, we tested whether cannabidiol affects the accumulation of hypoxia-inducible factor-1 alpha (HIF-1α) which plays a key role in the regulation of cellular adaptation to hypoxia and oxidative stress. We used 7-day-old mice randomly assigned to hypoxic or control groups. Immediately after hypoxia or control exposure, pups were randomly assigned to a vehicle or CBD treatment. 24 h later, they were decapitated and the brains were immediately removed and stored for further biochemical analyses.

We found that CBD reduced lipid peroxidation and prevented antioxidant depletion. For the first time, we also demonstrated that CBD upregulated HIF-1α protein level. This study indicates that CBD may effective agent in attenuating the detrimental consequences of perinatal asphyxia.”

https://pubmed.ncbi.nlm.nih.gov/38987284/

“Our results show that CBD applied in a short time after hypoxia attenuates hypoxia-induced oxidative stress, likely due to its antioxidant activity. To the best of our knowledge, this is also the first report showing that the post-hypoxia treatment with CBD increases the concentration of HIF-1α, which is directly involved in the maintenance of oxygen and iron homeostasis. This indicates that CBD is promising agent for new therapies developed for the treatment of hypoxic injury “

https://www.nature.com/articles/s41598-024-66599-5

From bench to bedside: the application of cannabidiol in glioma

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“Glioma is the most common malignant tumor in central nervous system, with significant health burdens to patients. Due to the intrinsic characteristics of glioma and the lack of breakthroughs in treatment modalities, the prognosis for most patients remains poor. This results in a heavy psychological and financial load worldwide.

In recent years, cannabidiol (CBD) has garnered widespread attention and research due to its anti-tumoral, anti-inflammatory, and neuroprotective properties.

This review comprehensively summarizes the preclinical and clinical research on the use of CBD in glioma therapy, as well as the current status of nanomedicine formulations of CBD, and discusses the potential and challenges of CBD in glioma therapy in the future.”

https://pubmed.ncbi.nlm.nih.gov/38987805/

“CBD, a non-psychoactive cannabinoid derived from the cannabis plant, has shown promising potential in the treatment of gliomas. Characterized by its safety, good tolerability, and absence of psychoactive effects, CBD induces apoptosis in glioma cells, mitochondrial dysfunction, and autophagy, thereby inhibiting the proliferation and invasion of glioma cells, suppressing the expression of GSCs properties, and promoting cell death. Additionally, it enhances the sensitivity to radiotherapy and chemotherapy while protecting neural functions, playing a significant role in the management of glioma symptoms. Preclinical and clinical studies have demonstrated encouraging anti-glioma activity. “

https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-024-05477-0

Potential analgesic effect of a novel cannabidiol nanocrystals powder for the treatment of neuropathic pain

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“Background: The current analgesics often prevent patients from getting effective treatment due to their adverse effects. Cannabidiol (CBD) is well tolerated, has few side effects and has been extensively investigated in analgesia. However, its oral bioavailability is extremely low. In order to solve this problem, we developed the cannabidiol nanocrystals (CBD-NC) in the earlier stage.

Methods: In this study, we evaluated the nociceptive behaviours associated with neuropathic pain (NP) induced by the spared nerve injury (SNI) model. Assessment of pain threshold was evaluated by paw withdraw threshold (PWT) and paw withdrawal latency (PWL). The improving effect on the motor dysfunction was determined by rota-rod testing. To assess the neuroprotective effect, nerve demyelination and expression of peripheral myelin protein PMP22 were measured with myelin sheath staining and western blotting. Protein expressions in microglia of spinal cord were tested by western blot to explore the underlying mechanism.

Results: Compared with the CBD oil solution, CBD-NC significantly reduced mechanical allodynia and thermal hyperalgesia in rats. CBD-NC could improve motor dysfunction induced by SNI in rats, significantly reverse the demyelination and increase the expression of the marker protein of peripheral myelin. Underlying spinal analgesic mechanism of microglia and related factors were preliminarily confirmed.

Conclusions: CBD-NC administration is an effective treatment for NP associated with SNI, and the analgesic effect of CBD-NC was significantly better than that of CBD oil sol. By contrast, CBD-NC has a fast-acting and long-term effect in the treatment of NP. Our study further supports the potential therapeutic effect of CBD-NC on NP.

Significance: The absolute bioavailability of the CBD-NC intramuscular injection formulation can reach 203.31%, which can solve the problem of low oral bioavailability. This research evaluated the therapeutic effect of CBD-NC on NP associated with the SNI model for the first time. All available date showed that whatever the analgesic or neuroprotective effect of CBD-NC, it was significantly better than that of CBD oil sol., which was consistent with the results of the pharmacokinetic. This research supports the initiation of more trials testing the efficacy of CBD-NC for treating NP.”

https://pubmed.ncbi.nlm.nih.gov/38982797/

https://onlinelibrary.wiley.com/doi/10.1002/ejp.2300