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

pubmed logo

“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

pubmed logo

“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


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

pubmed logo

“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

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

pubmed logo

“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

pubmed logo

“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

CANDI: A Web Server for Predicting Molecular Targets and Pathways of Cannabis-Based Therapeutics

pubmed logo

“Background: Cannabis sativa with a rich history of traditional medicinal use, has garnered significant attention in contemporary research for its potential therapeutic applications in various human diseases, including pain, inflammation, cancer, and osteoarthritis. However, the specific molecular targets and mechanisms underlying the synergistic effects of its diverse phytochemical constituents remain elusive. Understanding these mechanisms is crucial for developing targeted, effective cannabis-based therapies.

Methods: To investigate the molecular targets and pathways involved in the synergistic effects of cannabis compounds, we utilized DRIFT, a deep learning model that leverages attention-based neural networks to predict compound-target interactions. We considered both whole plant extracts and specific plant-based formulations. Predicted targets were then mapped to the Reactome pathway database to identify the biological processes affected. To facilitate the prediction of molecular targets and associated pathways for any user-specified cannabis formulation, we developed CANDI (Cannabis-derived compound Analysis and Network Discovery Interface), a web-based server. This platform offers a user-friendly interface for researchers and drug developers to explore the therapeutic potential of cannabis compounds.

Results: Our analysis using DRIFT and CANDI successfully identified numerous molecular targets of cannabis compounds, many of which are involved in pathways relevant to pain, inflammation, cancer, and other diseases. The CANDI server enables researchers to predict the molecular targets and affected pathways for any specific cannabis formulation, providing valuable insights for developing targeted therapies.

Conclusions: By combining computational approaches with knowledge of traditional cannabis use, we have developed the CANDI server, a tool that allows us to harness the therapeutic potential of cannabis compounds for the effective treatment of various disorders. By bridging traditional pharmaceutical development with cannabis-based medicine, we propose a novel approach for botanical-based treatment modalities.”

https://pubmed.ncbi.nlm.nih.gov/39149470/

https://www.researchsquare.com/article/rs-4744915/v1

The Medicinal Natural Products of Cannabis sativa Linn.: A Review

pubmed logo

“Cannabis sativa is known among many cultures for its medicinal potential. Its complexity contributes to the historical application of various parts of the plant in ethno-medicines and pharmacotherapy. 

C. sativa has been used for the treatment of rheumatism, epilepsy, asthma, skin burns, pain, the management of sexually transmitted diseases, difficulties during child labor, postpartum hemorrhage, and gastrointestinal activity. However, the use of C. sativa is still limited, and it is illegal in most countries. Thus, this review aims to highlight the biological potential of the plant parts, as well as the techniques for the extraction, isolation, and characterization of C. sativa compounds.

The plant produces a unique class of terpenophenolic compounds, called cannabinoids, as well as non-cannabinoid compounds. The exhaustive profiling of bioactive compounds and the chemical characterization and analysis of C. sativa compounds, which modern research has not yet fully achieved, is needed for the consistency, standardization, and the justified application of Cannabis sativa products for therapeutic purposes.

Studies on the clinical relevance and applications of cannabinoids and non-cannabinoid phenols in the prevention and treatment of life-threatening diseases is indeed significant. Furthermore, psychoactive cannabinoids, when chemically standardized and administered under medical supervision, can be the legal answer to the use of C. sativa.”

https://pubmed.ncbi.nlm.nih.gov/35268790/

https://www.mdpi.com/1420-3049/27/5/1689

Medical Cannabis Prescription Practices and Quality of Life in Thai Patients: A Nationwide Prospective Observational Cohort Study

pubmed logo

“Introduction: The legalization of cannabis in Thailand has renewed interest in its traditional medical use. This study aimed to explore the prescribing patterns of traditional practitioners and assess the impact of cannabis oil on patients’ quality of life, with a specific focus on comparing outcomes between cancer and non-cancer patients.

Methods: We conducted a prospective observational cohort study across 30 sites in 21 Thai provinces to analyze the use of “Ganja Oil,” a cannabis extract in 10% coconut oil, prescribed for symptoms like pain, anorexia, and insomnia across a diverse patient group, including cancer and migraines. Quality of life was assessed using the Edmonton Symptom Assessment Scale (ESAS) and EQ-5D-5L at baseline, 1, 2, and 3 months. The study included a predefined subgroup analysis to compare the effects on cancer versus non-cancer patients. Data management was facilitated through Research Electronic Data Capture (REDCap), with statistical analysis performed using Stata/MP.

Results: Among 21,284 participants, the mean age was 54.10 ± 15.32 years, with 52.49% being male. The baseline EQ-5D-5L index was 0.85 ± 0.24. Significant differences in EQ-5D-5L indices were seen between cancer patients (0.79 ± 0.32) and non-cancer patients (0.85 ± 0.23; p < 0.001). ESAS scores also differed significantly between these groups for all symptoms, except anxiety. The most frequent prescription of Ganja Oil was oral administration at bedtime (88.26%), with the predominant dosage being three drops daily, approximately 0.204 mg of tetrahydrocannabinol in total. Posttreatment, significant improvements were noted: the EQ-5D-5L index increased by 0.11 points (95% CI: 0.11, 0.11; p < 0.001) overall, 0.13 points (95% CI: 0.12, 0.14; p < 0.001) for cancer patients, and 0.11 points (95% CI: 0.10, 0.11; p < 0.001) for non-cancer patients. ESAS pain scores improved by -2.66 points (95% CI: -2.71, -2.61; p < 0.001) overall, -2.01 points (95% CI: -2.16, -1.87; p < 0.001) for cancer patients, and -2.75 points (95% CI: -2.80, -2.70; p < 0.001) for non-cancer patients, with similar significant improvements in other symptoms.

Conclusion: Our study indicates potential benefits of Ganja Oil for improving quality of life among Thai patients, as a complementary treatment. These findings must be viewed in light of the study’s design limitations. Further controlled studies are essential to ascertain its efficacy and inform dosing guidelines.”

https://pubmed.ncbi.nlm.nih.gov/39144529/

“This nationwide study marks a substantial step forward in the comprehension of medical cannabis, particularly highlighting its effectiveness in enhancing the quality of life for patients in a real-world setting. It underscores the importance of identifying optimal dosages and the potential benefits of integrating traditional medicine practices with conventional medicine approaches.”

https://karger.com/mca/article/7/1/125/909963/Medical-Cannabis-Prescription-Practices-and

Development of Delivery Systems with Prebiotic and Neuroprotective Potential of Industrial-Grade Cannabis sativa L

pubmed logo

“This study delves into the transformative effects of supercritical carbon dioxide (scCO2) cannabis extracts and prebiotic substances (dextran, inulin, trehalose) on gut bacteria, coupled with a focus on neuroprotection.

Extracts derived from the Białobrzeska variety of Cannabis sativa, utilising supercritical fluid extraction (SFE), resulted in notable cannabinoid concentrations (cannabidiol (CBD): 6.675 ± 0.166; tetrahydrocannabinol (THC): 0.180 ± 0.006; cannabigerol (CBG): 0.434 ± 0.014; cannabichromene (CBC): 0.490 ± 0.017; cannabinol (CBN): 1.696 ± 0.047 mg/gD). The assessment encompassed antioxidant activity via four in vitro assays and neuroprotective effects against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The extract boasting the highest cannabinoid content exhibited remarkable antioxidant potential and significant inhibitory activity against both enzymes. Further investigation into prebiotic deliveries revealed their proficiency in fostering the growth of beneficial gut bacteria while maintaining antioxidant and neuroprotective functionalities.

This study sheds light on the active compounds present in the Białobrzeska variety, showcasing their therapeutic potential within prebiotic systems. Notably, the antioxidant, neuroprotective, and prebiotic properties observed underscore the promising therapeutic applications of these extracts.

The results offer valuable insights for potential interventions in antioxidant, neuroprotective, and prebiotic domains. In addition, subsequent analyses of cannabinoid concentrations post-cultivation revealed nuanced changes, emphasising the need for further exploration into the dynamic interactions between cannabinoids and the gut microbiota.”

https://pubmed.ncbi.nlm.nih.gov/39124978/

https://www.mdpi.com/1420-3049/29/15/3574

Effects of ∆-9 tetrahydrocannabinol on the small intestine altered by high fructose diet: A Histopathological study

pubmed logo

“The consumption of fructose is increasing day by day. Understanding the impact of increasing fructose consumption on the small intestine is crucial since the small intestine processes fructose into glucose.

∆9-Tetrahydrocannabinol (THC), a key cannabinoid, interacts with CB1 and CB2 receptors in the gastrointestinal tract, potentially mitigating inflammation. Therefore, this study aimed to investigate the effects of the high-fructose diet (HFD) on the jejunum of rats and the role of THC consumption in reversing these effects.

Experiments were conducted on Sprague-Dawley rats, with the experimental groups as follows: control (C), HFD, THC, and HFD + THC. The HFD group received a 10% fructose solution in drinking water for 12 weeks. THC groups were administered 1.5 mg/kg/day of THC intraperitoneally for the last four weeks. Following sacrification, the jejunum was evaluated for mucus secretion capacity. IL-6, JNK, CB2 and PCNA expressions were assessed through immunohistochemical analysis and the ultrastructural alterations via transmission electron microscopy.

The results showed that fructose consumption did not cause weight gain but triggered inflammation in the jejunum, disrupted the cell proliferation balance, and increased mucus secretion in rats. Conversely, THC treatment displayed suppressed inflammation and improved cell proliferation balance caused by HFD. Ultrastructural examinations showed that the zonula occludens structures deteriorated in the HFD group, along with desmosome shrinkage. Mitochondria were found to be increased due to THC application following HFD.

In conclusion, the findings of this research reveal the therapeutic potential of THC in reversing HFD-related alterations and provide valuable insights for clinical application.”

https://pubmed.ncbi.nlm.nih.gov/39110194/

“Plant-derived cannabinoids and their synthetic analogs could be used medically. It is thought that THC could be used to prevent or reverse the effects of possible ultrastructural epithelial barrier damage caused by an HFD. In conclusion, our results show that high fructose consumption causes inflammation in the jejunum, increases mucus production, and disrupts the balance of cell proliferation. It has been determined that THC application is efficient in reversing these effects. In this context, new findings have been presented that THC can be a candidate as a therapeutic agent.”

https://link.springer.com/article/10.1007/s00418-024-02311-y