Beta-caryophyllene in psychiatric and neurological diseases: Role of blood-brain barrier

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“Beta-caryophyllene is an abundant terpene in cannabis, cinnamon, black pepper, cloves, and citrus fruit, delivering a striking, woody-spicy, like cloves and a sweet fruity aroma.

Beta-caryophyllene is a Food and Drug Administration-approved food additive with Generally Recognized as Safe status.

Interestingly, several biologic activities have been described for beta-caryophyllene, including anti-inflammatory and analgesic effects, neuroprotection against cerebral ischemia and neuronal injury, protection of neurovascular unit against oxidative damage, glial activation and neuroinflammation and anticonvulsant effects.

In this chapter, we intend to review the beneficial effects of beta-caryophyllene in the context of psychiatric and neurological diseases. Also, we will analyze the possibility that the blood-brain-barrier may be a central target underlying the beneficial actions of beta-caryophyllene.”

https://pubmed.ncbi.nlm.nih.gov/39029971/

“Compelling evidence support the therapeutic potential of beta-caryophyllene in a broad range of conditions. Moreover, this natural compound is already in use with food and cosmetic industries. Altogether, these features may enable its application as a therapeutic adjuvant to conventional drug therapy for often difficult to treat psychiatric and neurological diseases in the near future. “

https://www.sciencedirect.com/science/article/abs/pii/S0083672924000074?via%3Dihub

“Beta-caryophyllene is a dietary cannabinoid”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2449371/

Long-term stability and bactericidal properties of galenic formulations of Cannabis sativa oils

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“The long-term stability in real and accelerated time for galenic oils based on full-spectrum cannabis has been studied, using sesame oil as a dilutant. Sesame oil is one of the most used vehicles in the cannabis pharmaceutical industry due to the costs and increased oral bioavailability of cannabinoids. The real-time assays conducted at 25 °C over twelve months demonstrated high stability and showed no significant changes in the composition of cannabinoids, total polyphenols, flavonoids, or antioxidant capacity. In these studies, it was observed that there was no development of microorganisms compromising the stability of the oils over a year. The three oil varieties exhibited a high bactericidal capacity against E. coli, S. aureus, and P. larvae.”

https://pubmed.ncbi.nlm.nih.gov/39025316/

Use and perceptions of Cannabidiol among individuals in treatment for opioid use disorder

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“Background: Cannabidiol (CBD) is a widely available cannabis product with many claims as to potential health benefits including alleviating symptoms related to opioid use disorder (OUD). However, little is known as to how individuals with OUD perceive CBD, to what extent they may already be using CBD, and for what purposes.

Methods: A survey was conducted among individuals receiving treatment for OUD at the Addiction Institute of Mount Sinai in New York City from July 2021 to August 2023. The survey consisted of demographic questions, questions about opioid use, CBD use, and perceptions regarding CBD. Statistical analysis using ordinal logistic regression was employed to compare perceptions between CBD users and non-users while adjusting for age and race.

Results: Among 587 respondents, 550 completed the survey. Among all survey completers, 129 (23%) reported a history of using CBD for a variety of reasons including: anxiety (81, 62.8%), pain (65, 50.4%), sleep (63, 48.8%), depression (62, 48.1%), recreational purposes (32, 24.8%), or for other reasons (8, 6.2%). Of note, 22 (17.1%) respondents reported using CBD to control their addiction and 54 (41.9%) reported using CBD to ease opioid withdrawal symptoms. CBD users demonstrated more positive perceptions regarding its legality (β = 0.673, OR = 1.960, 95% CI [1.211, 3.176], p = .006), social acceptance (β = 0.718, OR = 2.051, 95% CI [1.257, 3.341], p = .004), and therapeutic potential compared to non-users. CBD users also had a more positive view of its potential future role in managing addiction (β = 0.613, OR = 1.846, 95% CI [1.181, 2.887], p = .007).

Conclusions: This study highlights a significant association between CBD usage and progressive views regarding CBD among individuals with OUD, suggesting a growing interest in CBD as a potential adjunctive therapy for individuals in substance use treatment. Some patients are already using CBD for anxiety, pain, sleep, depression, or as a harm reduction intervention to control their addiction or for opioid withdrawal symptoms. These findings underscore the importance of integrating patient perspectives into future research and treatment strategies involving CBD in the context of OUD.”

https://pubmed.ncbi.nlm.nih.gov/39020418/

“The current survey study provides valuable insights into the usage and perceptions of CBD among individuals in treatment for OUD. The findings reveal that some patients are already using CBD for a variety of reasons including anxiety, pain, sleep, depression, or as a harm reduction intervention to control their opioid use or minimize opioid withdrawal symptoms. This is often done without the knowledge of their healthcare providers. Respondents overall had a positive view of CBD suggesting a growing interest in its use as a potential adjunctive therapy for individuals with substance use disorders. The results also emphasize the importance of incorporating patient real-world experience and opinions into the development of future research and treatment approaches. By doing so, we can create more effective, patient-centered strategies that address the complexities of the opioid overdose crisis. Robust clinical research and clear medical guidelines are essential to harness the full potential of CBD as a harm reduction tool, ultimately improving outcomes for those struggling with OUD.”

https://harmreductionjournal.biomedcentral.com/articles/10.1186/s12954-024-01051-5

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

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

Full-spectrum cannabidiol reduces UVB damage through the inhibition of TGF-β1 and the NLRP3 inflammasome

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“The thermodynamic characteristics, antioxidant potential, and photoprotective benefits of full-spectrum cannabidiol (FS-CBD) against UVB-induced cellular death were examined in this study. In silico analysis of CBD showed antioxidant capacity via proton donation and UV absorption at 209.09, 254.73, and 276.95 nm, according to the HAT and SPLET methodologies. FS-CBD protected against UVB-induced bacterial death for 30 min. FS-CBD protected against UVB-induced cell death by 42% (1.5 μg/mL) and 35% (3.5 μg/mL) in an in vitro keratinocyte cell model. An in vivo acute irradiated CD-1et/et mouse model (UVB-irradiated for 5 min) presented very low photoprotection when FS-CBD was applied cutaneously, as determined by histological analyses. In vivo skin samples showed that FS-CBD regulated inflammatory responses by inhibiting the inflammatory markers TGF-β1 and NLRP3. The docking analysis showed that the CBD molecule had a high affinity for TGF-β1 and NLRP3, indicating that protection against inflammation might be mediated by blocking these proinflammatory molecules. This result was corroborated by the docking interactions between CBD and TGF-β1 and NLRP3, which resulted in a high affinity and inhibition of both proteins The present work suggested a FS-CBD moderate photoprotective agent against UVB light-induced skin damage and that this effect is partially mediated by its anti-inflammatory activity.”

https://pubmed.ncbi.nlm.nih.gov/38958000/

https://onlinelibrary.wiley.com/doi/10.1111/php.13993

Uncovering the antiinflammatory potential of Lactiplantibacillus Plantarum fermented Cannabis Sativa L seeds

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“Inflammation acts as a dual role in disease initiation and progression, while Cannabis sativa L. (hemp) seeds, known for their abundance of anti-inflammatory phytochemicals, present a promising food source. Additionally, fermentation may optimize the food matrix, thereby augmenting its developmental prospects.

This study explores the anti-inflammatory potential of hemp seeds fermented with 10 different probiotic strains.

Among these, Lactiplantibacillus plantarum fermented hemp seeds (FHS) demonstrated a significant anti-inflammatory ability, accompanied by a reduction in the expression of critical inflammatory markers such as TLR4, NF-κBp65, and iNOS. Moreover, there is a noteworthy dose-dependent inhibition of inflammatory cytokines TNF-α, IL-6, IL-1β, and NO within a concentration range of 50 to 500 µg/mL. Subsequently, metabolomics analysis using UHPLC-QTOF-MS highlighted significant metabolic alterations in FHS compared to raw hemp seeds (RHS). Through multivariate, univariate, and correlation analyses, indolelactic acid (IA) and homovanillic acid (HVA) emerged as the main anti-inflammatory metabolites in FHS. Validation via HPLC confirmed the concentration of IA and HVA in RHS and FHS and both organic acids demonstrated lower IC50 values for TNF-α, IL-1β, IL-6, IL-18, and NO inhibition, showcasing their potent anti-inflammatory abilities. Furthermore, in vitro gastro-intestinal digestion coupled with the Caco-2 cell monolayer model validates the uptake and bioaccessibility of FHS, further affirming IA and HVA as major anti-inflammatory compounds.

Overall, this research sets the stage for the development of novel hemp seed-based products targeting inflammation-associated disorders.”

https://pubmed.ncbi.nlm.nih.gov/38944646/

“Cannabis sativa L. (hemp) seeds have recently gained global recognition as a potentially valuable food source due to their rich protein, oil necessary to meet human dietary demands. Based on these findings, we concluded that L. plantarum fermentation significantly enhances the anti-inflammatory activity of hemp seeds.”

https://www.nature.com/articles/s41538-024-00285-8

Cannabidiol alleviates right ventricular fibrosis by inhibiting the transforming growth factor β pathway in monocrotaline-induced pulmonary hypertension in rats

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“Cannabidiol (CBD) is a non-intoxicating compound of Cannabis with anti-fibrotic properties. Pulmonary hypertension (PH) is a disease that can lead to right ventricular (RV) failure and premature death.

There is evidence that CBD reduces monocrotaline (MCT)-induced PH, including reducing right ventricular systolic pressure (RVSP), vasorelaxant effect on pulmonary arteries, and decreasing expression of profibrotic markers in the lungs.

The aim of our study was to investigate the effect of chronic administration of CBD (10 mg/kg daily for 21 days) on profibrotic parameters in the RVs of MCT-induced PH rats.

In MCT-induced PH, we found an increase in profibrotic parameters and parameters related to RV dysfunction, i.e. plasma pro-B-type natriuretic peptide (NT-proBNP), cardiomyocyte width, interstitial and perivascular fibrosis area, amount of fibroblasts and fibronectin, as well as overexpression of the transforming growth of factor β1 (TGF-β1), galectin-3 (Gal-3), suppressor of mothers against decapentaplegic 2 (SMAD2), phosphorylated SMAD2 (pSMAD2) and alpha-smooth muscle actin (α-SMA). In contrast, vascular endothelial cadherin (VE-cadherin) levels were decreased in the RVs of MCT-induced PH rats.

Administration of CBD reduced the amount of plasma NT-proBNP, the width of cardiomyocytes, the amount of fibrosis area, fibronectin and fibroblast expression, as well as decreased the expression of TGF-β1, Gal-3, SMAD2, pSMAD2, and increased the level of VE-cadherin.

Overall, CBD has been found to have the anti-fibrotic potential in MCT-induced PH. As such, CBD may act as an adjuvant therapy for PH, however, further detailed investigations are recommended to confirm our promising results.”

https://pubmed.ncbi.nlm.nih.gov/37187449/

“CBD may be used in the future as add-on therapy in the treatment of PH.”

https://www.sciencedirect.com/science/article/pii/S0925443923001199?via%3Dihub

“CBD has potential to boost heart function in PH patients: Early study”

Cannabidiol inhibits lung proliferation in monocrotaline-induced pulmonary hypertension in rats

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“Cannabidiol (CBD) is a safe and well-tolerated plant-derived drug with anti-proliferative properties.

Pulmonary hypertension (PH) is a rapidly progressive and still incurable disease.

CBD diminishes monocrotaline (MCT)-induced PH, including reduced right ventricular systolic pressure, pulmonary vascular hypertrophy, and right ventricular remodeling.

The aim of our study was to investigate the effect of chronic administration of CBD (10 mg/kg once daily for 21 days) on selected remodeling parameters in the lung of MCT-induced PH rats.

In MCT-induced PH, we found an increase in profibrotic parameters, e.g., transforming growth factor β1 (TGF-β1), galectin-3 (Gal-3), procollagen I, collagen I, C-propeptide, matrix metalloproteinase 9 (MMP-9) and an increased number of mast cells. In our study, we observed that the TGF-β1, Gal-3, procollagen I, collagen I, C-propeptide, and mast cell levels in lung tissue were decreased after CBD administration to MCT-treated rats.

In summary, CBD treatment has an anti-proliferative effect on MCT-induced PH. Given the beneficial multidirectional effects of CBD on PH, we believe that CBD can be used as an adjuvant PH therapy, but this argument needs to be confirmed by clinical trials.”

https://pubmed.ncbi.nlm.nih.gov/36634588/

“CBD may be used in the future as an adjuvant therapy in the treatment of PH.”

https://www.sciencedirect.com/science/article/pii/S0753332223000227?via%3Dihub

Cannabidiol attenuates pulmonary arterial hypertension by improving vascular smooth muscle cells mitochondrial function

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“Rationale: Pulmonary arterial hypertension (PAH) is a chronic disease associated with enhanced proliferation of pulmonary artery smooth muscle cells (PASMCs) and dysfunctional mitochondria, and the clinical therapeutic option for PAH is very limited. Recent studies showed that cannabidiol (CBD), a non-psychoactive constituent of cannabinoids, possessed antioxidant effect towards several cardiovascular diseases, whereas the mechanistic effect of CBD in PAH is unknown. 

Methods: In this study, the effects of CBD in PAH were determined by analyzing its preventive and therapeutic actions in PAH rodent models in vivo and PASMCs’ proliferation test in vitro. Additionally, CBD’s roles in mitochondrial function and oxidant stress were also assessed in PASMCs. 

Results: We found that CBD reversed the pathological changes observed in both Sugen-hypoxia and monocrotaline-induced PAH rodent models in a cannabinoid receptors-independent manner. Our results also demonstrated that CBD significantly inhibited the PASMCs’ proliferation in PAH mice with less inflammation and reactive oxygen species levels. Moreover, CBD alleviated rodent PAH by recovering mitochondrial energy metabolism, normalizing the hypoxia-induced oxidant stress, reducing the lactate overaccumulation and abnormal glycolysis. 

Conclusions: Taken together, these findings confirm an important role for CBD in PAH pathobiology.”

https://pubmed.ncbi.nlm.nih.gov/33859746/

“We demonstrated that CBD inhibited the hyperproliferation of PASMCs, recovered the function of mitochondria, alleviated the oxidant stress in PASMCs and inhibited the excessive glycolysis, accompanied by metabolic improvement (Graphical abstract). Consistently, CBD successfully ameliorated hypoxia-induced PAH in mice and MCT-induced PAH in rats. Taken together, our study strongly suggested that CBD might provide a promising novel potential for the treatment of PAH.”

https://www.thno.org/v11p5267.htm