Monthly Archives: August 2024

Cannabinoid Therapy in Athletics: A Review of Current Cannabis Research to Evaluate Potential Real-World Cannabinoid Applications in Sport

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“The increasing legalization of Cannabis sativa plant products has sparked growing interest in their therapeutic applications.

Prohibition laws established in 1937 hindered formal research on cannabis, a plant with cultural and medicinal roots dating back to 2700 BC in Chinese history.

Despite regulatory hurdles, published research on cannabis has emerged; yet elite athletes remain an underrepresented population in these studies. Athletes, known for exploring diverse substances to optimize performance, are drawn to the potential benefits of cannabinoid therapy, with anecdotal reports suggesting positive effects on issues ranging from anxiety to brain injuries.

This review aims to evaluate empirical published cannabis research with a specific focus on its potential applications in athletics. The changing legal landscape, especially the removal of cannabis from drug testing programs in leagues such as the National Basketball Association (NBA), and endorsements by Major League Baseball (MLB) for cannabinoid products and the National Football League (NFL) for cannabis research, reflects a shift in the acceptability of such substances in sports. However, stigma, confusion, and a lack of education persist, hindering a cohesive understanding among sports organizations, including business professionals, policymakers, coaches, and medical/training staff, in addition to athletes themselves. Adding to the confusion is the lack of consistency with cannabinoid regulations from sport to sport, within or out of competition, and with cannabis bioactive compounds.

The need for this review is underscored by the evolving attitudes toward cannabinoids in professional sports and the potential therapeutic benefits or harms they may offer. By synthesizing current cannabis research, this review aims to provide a comprehensive understanding of the applications and implications of cannabinoid use in the realm of athletics.”

https://pubmed.ncbi.nlm.nih.gov/39168949/

FDA-approved cannabidiol [Epidiolex®] alleviates Gulf War Illness-linked cognitive and mood dysfunction, hyperalgesia, neuroinflammatory signaling, and declined neurogenesis

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“Background: Chronic Gulf War Illness (GWI) is characterized by cognitive and mood impairments, as well as persistent neuroinflammation and oxidative stress. This study aimed to investigate the efficacy of Epidiolex®, a Food and Drug Administration (FDA)-approved cannabidiol (CBD), in improving brain function in a rat model of chronic GWI.

Methods: Six months after exposure to low doses of GWI-related chemicals [pyridostigmine bromide, N,N-diethyl-meta-toluamide (DEET), and permethrin (PER)] along with moderate stress, rats with chronic GWI were administered either vehicle (VEH) or CBD (20 mg/kg, oral) for 16 weeks. Neurobehavioral tests were conducted on 11 weeks after treatment initiation to evaluate the performance of rats in tasks related to associative recognition memory, object location memory, pattern separation, and sucrose preference. The effect of CBD on hyperalgesia was also examined. The brain tissues were processed for immunohistochemical and molecular studies following behavioral tests.

Results: GWI rats treated with VEH exhibited impairments in all cognitive tasks and anhedonia, whereas CBD-treated GWI rats showed improvements in all cognitive tasks and no anhedonia. Additionally, CBD treatment alleviated hyperalgesia in GWI rats. Analysis of hippocampal tissues from VEH-treated rats revealed astrocyte hypertrophy and increased percentages of activated microglia presenting NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) complexes as well as elevated levels of proteins involved in NLRP3 inflammasome activation and Janus kinase/signal transducers and activators of the transcription (JAK/STAT) signaling. Furthermore, there were increased concentrations of proinflammatory and oxidative stress markers along with decreased neurogenesis. In contrast, the hippocampus from CBD-treated GWI rats displayed reduced levels of proteins mediating the activation of NLRP3 inflammasomes and JAK/STAT signaling, normalized concentrations of proinflammatory cytokines and oxidative stress markers, and improved neurogenesis. Notably, CBD treatment did not alter the concentration of endogenous cannabinoid anandamide in the hippocampus.

Conclusions: The use of an FDA-approved CBD (Epidiolex®) has been shown to effectively alleviate cognitive and mood impairments as well as hyperalgesia associated with chronic GWI. Importantly, the improvements observed in rats with chronic GWI in this study were attributed to the ability of CBD to significantly suppress signaling pathways that perpetuate chronic neuroinflammation.”

https://pubmed.ncbi.nlm.nih.gov/39169440/


CBD oil by-product (Hemp flakes): Evaluation for nutritional composition, heavy metals and functionality as a food ingredient

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“Background: The recent interest among consumers in industrial hemp due to health and wellness benefits has led to several products from industrial hemp, including cannabidiol (CBD) oil. CBD oil extraction from hemp buds and flowers generates by-product biomass (hemp flakes), often posing disposal challenges and with little or no applications. We hypothesized that hemp flakes possess residual compounds with nutritional and health value that could be used to improve utilization.

Methods: Locally sourced hemp flakes were compared to three commercial hemp protein products. The nutritional composition (proximate analysis), heavy metals (Al, Cu, As, Pb, Co, Cd), and functional composition (phenolic and antioxidant properties-total phenolic compounds (TPC), total flavonoid compounds (TFC), ferric reducing antioxidant potential (FRAP), 1,1-diphenyl-1-picrylhydrazyl (DPPH), Trolox equivalent antioxidant capacity (TEAC)), (CBD, cannabiodiolic acid-CBDA, cannabichromene-CBC, cannabigerol-CBG, and cannabinol-CBN) contents were determined and compared.

Findings: Hemp flakes had a similar nutritional composition to commercial hemp protein products, with heavy metal levels within FDA allowed limits. The by-product had significantly higher CBDA levels than commercial products. Overall, hemp flakes had comparable nutrient composition and antioxidant capabilities. Based on the protein composition of hemp flakes (31.62 %) versus the highest commercial product (43 %), hemp flakes are an acceptable functional food ingredient.”

https://pubmed.ncbi.nlm.nih.gov/39165951/

“It is predicted that by 2050, the world’s population will reach 9 billion, and a sustained food supply will be a concern; therefore, it is appropriate to examine alternatives, including the exploration of agricultural waste materials. Hemp flakes as a by-product from CBD oil extraction could be utilized due to their nutritional and functional value. The hemp flake used in this work demonstrated to hold nutritional and health components comparable to related commercial products. The antioxidant levels showed variations attributed to the source of hemp material and solvent extraction method. Hemp flakes exhibited high and similar antioxidant properties as measured by TPC, TFC, FRAP, and TEAC and possessed comparable radical scavenging properties as measured by DPPH. The hemp by-product showed comparative amounts of cannabinoids with the highest content of cannabidiolic acid, which is known to break down to cannabidiol and possess functional benefits. Further, the results of this work have exemplified that hemp flakes generated from CBD oil extraction have a considerable nutritional and functional value that supports its potential to be incorporated in food preparations as an ingredient. It was also established that the hemp flakes contained levels below the permissible levels of heavy metals in foods, according to health and environmental agencies. It is concluded that the by-product from CBD oil extraction could be utilized as an ingredient in food processing, such as a composite with other ingredients to complement nutrition and health functionality for consumers.”

https://www.cell.com/heliyon/fulltext/S2405-8440(24)11217-0?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2405844024112170%3Fshowall%3Dtrue


Cannabidiol Enhances the Anticancer Activity of Etoposide on Prostate Cancer Cells

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“Introduction: Cannabis sativa extract has been used as an herbal medicine since ancient times. It is one of the most researched extracts, especially among supportive treatments against cancer. Prostate cancer is one of the most frequently diagnosed cancer types in men worldwide and an estimated 288,300 new cases were diagnosed in 2023. Today, many advanced therapeutic approaches are used for prostate cancer, such as immunotherapy and chemotherapy, but acquired drug resistance, long-term drug usage and differentiation of cancer cells mostly restricted the efficiency of therapies. Therefore, it is thought that the use of natural products to overcome these limitations and improve the effectiveness of existing therapies may offer promising approaches. The present study focused on the investigation of the possible enhancer role of cannabidiol (CBD), which is a potent ingredient compound of Cannabis, on the chemotherapeutic agent etoposide in prostate cancer cells. 

Methods: Herein, we tested the potentiator role of CBD on etoposide in prostate cancer cells by testing the cytotoxic effect, morphological alterations, apoptotic effects, autophagy, unfolded protein response (UPR) signaling, endoplasmic reticulum-associated degradation mechanism (ERAD), angiogenic and androgenic factors, and epithelial-mesenchymal transition (EMT). In addition, we examined the combined treatment of CBD and etoposide on colonial growth, migrative, invasive capability, 3D tumor formation, and cellular senescence. 

Results: Our findings demonstrated that cotreatment of etoposide with CBD importantly suppressed autophagic flux and induced ERAD and UPR signaling in LNCaP cells. Also, CBD strongly enhanced the etoposide-mediated suppression of androgenic signaling, angiogenic factor VEGF-A, protooncogene c-Myc, EMT, and also induced apoptosis through activation caspase-3 and PARP-1. Moreover, coadministration markedly decreased tumorigenic properties, such as proliferative capacity, colonial growth, migration, and 3D tumor formation and also induced senescence. Altogether, our data revealed that CBD has a potent enhancer effect on etoposide-associated anticancer activities. 

Conclusion: The present study suggests that the use of CBD as a supportive therapy in existing chemotherapeutic approaches may be a promising option, but this effectiveness needs to be investigated on a large scale.”

https://pubmed.ncbi.nlm.nih.gov/39161998/

https://www.liebertpub.com/doi/10.1089/can.2023.0284

A National Survey of Marijuana Use Among U.S. Adults According to Obesity Status, 2016-2022

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“Background and Objective: Research has linked marijuana use with lower body mass index (BMI). The current study explores the correlation between marijuana use on BMI in the general U.S. population. It reports the prevalence of marijuana in adults in relation to BMI, overall and across the levels of important variables. 

Materials and Methods: This study used a probability sample of U.S. adults 18 years of age and older from the 2016 through 2022 Behavioral Risk Factor Surveillance System, a telephone-administered survey. The survey collects data from a representative sample regarding health-related risk behaviors, chronic health conditions, and use of preventive services. The primary outcome variables are current (at least once in the last 30 days) and daily (at least 20 of the last 30 days) marijuana use. 

Results: The study sample consists of 735,921 participants in the surveys that completed the optional module on marijuana use. Prevalence of marijuana use in adults doubled during the study period (7.48% to 14.91%). The increase directly corresponds with a shift toward legalization of medical and recreational marijuana. On average, the prevalence of use is 9% higher when medical marijuana is legal and 81% higher when recreational marijuana is legal (vs. not legal). For obese individuals, prevalence of current marijuana use is 35% lower than for nonobese individuals on average. Lower prevalence of marijuana use in obese individuals is consistently observed across the levels of certain demographic variables, employment status, tobacco smoking history, marijuana legalization status, and certain medical conditions (asthma, arthritis, and depression). In 2022, the adjusted odds of current or daily marijuana use are significantly lower and similar among obese (vs. non-obese) (0.68, 0.69, respectively), such that reduced obesity does not require daily use. Similarly, the adjusted odds of current marijuana use decrease in similar fashion to daily marijuana use with higher BMI weight classification. 

Conclusion: Marijuana use is correlated with lower BMI. As legalization and prevalence of the drug in the U.S. increases, the prevalence of obesity may decline. However, clinicians should view this outcome along with the known health risks associated with marijuana use.”

https://pubmed.ncbi.nlm.nih.gov/39158998/

https://www.liebertpub.com/doi/10.1089/can.2024.0069

β-Caryophyllene mitigates ischemic stroke-induced white matter lesions by inhibiting pyroptosis

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“β-Caryophyllene (BCP), a selective agonist for cannabinoid receptor 2 (CB2R), has demonstrated promising protective effects in various pathological conditions. However, the neuroprotective effects of BCP on white matter damage induced by ischemic stroke have not been elucidated previously.

In this study, we find that BCP not only improves sensorimotor and cognitive function via CB2R but also mitigates white matter lesions in mice following ischemic stroke. Furthermore, BCP enhances the viability of MO3.13 oligodendrocytes after oxygen-glucose deprivation and reoxygenation (OGD/R), attenuating OGD/R-induced cellular damage and pyroptosis. Notably, these protective effects of BCP are partially enhanced by the NLRP3 inhibitor MCC950 and counteracted by the NLRP3 activator nigericin. In addition, nigericin significantly exacerbates neurological outcomes and increases white matter lesions following BCP treatment in middle cerebral artery occlusion (MCAO) mice.

These results suggest that BCP may ameliorate neurological deficits and white matter damage induced by cerebral ischemia through inhibiting NLRP3-mediated pyroptosis.”

https://pubmed.ncbi.nlm.nih.gov/39159913/

“In conclusion, our study provides compelling evidence that BCP can enhance motor and cognitive function outcomes via activating CB2R, as well as promote white matter integrity after ischemic stroke. Significantly, this research establishes, for the first time, the crucial role of inhibiting NLRP3-mediated pyroptosis in the therapeutic effects of BCP post-ischemic stroke.”

https://www.sciencedirect.com/science/article/abs/pii/S0014482724003057?via%3Dihub

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

“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

Potential Neuroprotective Effect of the Endocannabinoid System on Parkinson’s Disease

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“Parkinson’s disease (PD) is a neurodegenerative disorder characterized by alterations in motor capacity resulting from a decrease in the neurotransmitter dopamine due to the selective death of dopaminergic neurons of the nigrostriatal pathway. Unfortunately, conventional pharmacological treatments fail to halt disease progression; therefore, new therapeutic strategies are needed, and currently, some are being investigated.

The endocannabinoid system (ECS), highly expressed in the basal ganglia (BG) circuit, undergoes alterations in response to dopaminergic depletion, potentially contributing to motor symptoms and the etiopathogenesis of PD. Substantial evidence supports the neuroprotective role of the ECS through various mechanisms, including anti-inflammatory, antioxidative, and antiapoptotic effects. Therefore, the ECS emerges as a promising target for PD treatment.

This review provides a comprehensive summary of current clinical and preclinical evidence concerning ECS alterations in PD, along with potential pharmacological targets that may exert the protection of dopaminergic neurons.”

https://pubmed.ncbi.nlm.nih.gov/39104613/

“Considering current evidence, the ECS emerges as a promising therapeutic target for managing PD, primarily owing to its neuroprotective effects, prominently mediated through anti-inflammatory mechanisms. This is particularly significant since neuroinflammation stands out as a hallmark of PD, and extensive preclinical studies have consistently demonstrated that modulating this inflammatory process mitigates the progression of dopaminergic neuronal death.”

https://onlinelibrary.wiley.com/doi/10.1155/2024/5519396

Oral Cannabis Extract for Secondary Prevention of Chemotherapy-Induced Nausea and Vomiting: Final Results of a Randomized, Placebo-Controlled, Phase II/III Trial

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“Purpose: The aim of this randomized, placebo-controlled, two-stage, phase II/III trial was to determine the efficacy of an oral cannabis extract in adults with refractory nausea and/or vomiting during moderately or highly emetogenic, intravenous chemotherapy despite guideline-consistent antiemetic prophylaxis. Here, we report results of the prespecified combined analysis including the initial phase II and subsequent phase III components.

Patients and methods: Study treatment consisted of oral capsules containing either tetrahydrocannabinol 2.5 mg plus cannabidiol 2.5 mg capsules (THC:CBD) or matching placebo, taken three times a day from days -1 to 5, in addition to guideline-consistent antiemetics. The primary measure of effect was the difference in the proportions of participants with no vomiting or retching and no use of rescue medications (a complete response) during hours 0-120 after the first cycle of chemotherapy on study (cycle A).

Results: We recruited 147 evaluable of a planned 250 participants from 2016 to 2022. Background antiemetic prophylaxis included a corticosteroid and 5-hydroxytryptamine antagonist in 97%, a neurokinin-1 antagonist in 80%, and olanzapine in 10%. THC:CBD compared with placebo improved the complete response rate from 8% to 24% (absolute difference 16%, 95% CI, 4 to 28, P = .01), with similar effects for absence of significant nausea, use of rescue medications, daily vomits, and the nausea scale on the Functional Living Index-Emesis quality-of-life questionnaire. More frequent bothersome adverse events of special interest included sedation (18% v 7%), dizziness (10% v 0%), and transient anxiety (4% v 1%). There were no serious adverse events attributed to THC:CBD.

Conclusion: THC:CBD is an effective adjunct for chemotherapy-induced nausea and vomiting despite standard antiemetic prophylaxis, but was associated with additional adverse events. Drug availability, cultural attitudes, legal status, and preferences may affect implementation. Future analyses will evaluate the cost-effectiveness of THC:CBD.”

https://pubmed.ncbi.nlm.nih.gov/39151115/

“In conclusion, an oral formulation of THC:CBD was an effective adjunct to standard antiemetics for prevention and treatment of refractory CINV, with adverse effects including sedation and dizziness, but no increase in serious adverse events. Our data support the claim that oral THC:CBD is an effective and safe option for the prevention of refractory CINV. Availability, access, affordability, cultural attitudes, societal barriers, and legal barriers may limit implementation.”

https://ascopubs.org/doi/10.1200/JCO.23.01836

Perceptions in Orthopedic Surgery on the Use of Cannabis in Treating Pain: A Survey of Musculoskeletal Trauma Patients-Results From the Canadian POSIT Study

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“Objectives: To evaluate the patient-reported expectations regarding cannabis for pain following musculoskeletal (MSK) trauma and patients’ perceptions and attitudes regarding its use.

Design: A cross-sectional retrospective survey-based study.

Setting: Three orthopaedic clinics in Ontario (Level-1 trauma center, Level-2 trauma center, rehabilitation clinic).

Patients selection criteria: Adult patients presenting to the clinics from January 24, 2018, to March 7, 2018, with traumatic MSK injuries (fractures/dislocations and muscle/tendon/ligament injury) were administered an anonymous questionnaire on cannabis for MSK pain.

Outcome measures and comparisons: Primary outcome measure was the patients’ perceived effect of cannabis on MSK pain, reported on a continuous pain scale (0%-100%, 0 being no pain, and 100 unbearable pain). Secondary outcomes included preferences, such as administration route, distribution method, timing, and barriers (lack of knowledge, concerns for side effects/addiction, moral/religious opposition, etc.) regarding cannabis use.

Results: In total, 440 patients were included in this study, 217 (49.3%) of whom were female and 222 (50.5%) were male, with a mean age of 45.6 years (range 18-92 years, standard deviations 15.6). Patients estimated that cannabis could treat 56.5% (95% CI 54.0%-59.0%) of their pain and replace 46.2% (95% CI 42.8%-49.6%) of their current analgesics. Nearly one-third (131/430, 30.5%) reported that they had used medical cannabis and more than one-quarter (123/430, 28.6%) used it in the previous year. Most felt that cannabis may be beneficial to treat pain (304/334, 91.0%) and reduce opioid use (293/331, 88.5%). Not considering using cannabis for their injury (132/350, 37.7%) was the most common reason for not discussing cannabis with physicians. Higher reported pain severity (β = 0.2/point, 95% CI 0.1-0.3, P = 0.005) and previous medical cannabis use were associated with higher perceived pain reduction (β = 11.1, 95% CI 5.4-16.8, P < 0.001).

Conclusions: One in 3 orthopaedic trauma patients used medical cannabis. Patients considered cannabis could potentially be an effective option for managing traumatic MSK pain and believed that cannabis could reduce opioid usage following acute musculoskeletal trauma. These data will help inform clinicians discussing medical cannabis usage with orthopaedic trauma patients moving forward.”

https://pubmed.ncbi.nlm.nih.gov/39150305/

https://journals.lww.com/jorthotrauma/abstract/2024/09000/perceptions_in_orthopedic_surgery_on_the_use_of.12.aspx

Integrating Lipidomics, Metabolomics, and Network Pharmacology to Reveal the Mechanism of Cannabidiol against Inflammation in High-Fat, High-Cholesterol Diet-Induced Mice

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“Inflammation plays a critical role in the development of numerous diseases.

Cannabidiol (CBD), found in hemp, exhibits significant pharmacological activities. Accumulating evidence suggests that CBD has anti-inflammatory and cardiovascular protection effects, but the potential mechanisms require further exploration.

In this study, we aimed to reveal the mechanisms of CBD against high-fat, high-cholesterol (HFC) diet-induced inflammation combining metabolomics with network pharmacology.

First, plasma lipidomics results indicated that oxidized lipids could serve as potential biomarkers for HFC diet-induced inflammation, and CBD reversed the elevated levels of oxidized lipids. The HFC diet was also found to enhance intestinal permeability, facilitating the entry of lipopolysaccharides (LPSs) into the circulatory system and subsequently increasing systemic inflammation.

Additionally, cell metabolomic results indicated that CBD could reverse 10 important differential metabolites in LPS-induced RAW 264.7 cells. Using network pharmacology, we identified 49 core targets, and enrichment analysis revealed that arachidonic acid was the most significantly affected by CBD, which was closely associated with inflammation.

Further integrated analysis focused on three key targets, including PTGS2, ALOX5, and ALOX15. Molecular docking showed high affinities between key targets and CBD, and qPCR further demonstrated that CBD could reverse the mRNA expression of these key targets in RAW 264.7 cells.

Collectively, this finding integrates lipidomics and metabolomics with network pharmacology to elucidate the anti-inflammatory effects of CBD and validates key therapeutic targets.”

https://pubmed.ncbi.nlm.nih.gov/39150414/

https://pubs.acs.org/doi/10.1021/acs.jafc.4c04994