Evaluation of the efficacy, safety, and pharmacokinetics of nanodispersible cannabidiol oral solution (150 mg/mL) versus placebo in mild to moderate anxiety subjects: A double blind multicenter randomized clinical trial

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“Background: Anxiety disorders, an increasingly prevalent global mental health illness, affected approximately 301 million individuals worldwide in 2019. There is an unmet need for the treatment of anxiety disorders, as current therapies are associated with limited response rates, residual symptoms, and adverse effects.

Objectives: To evaluate the efficacy, safety, and pharmacokinetics of nanodispersible cannabidiol (CBD) oral solution versus placebo for the treatment of mild to moderate anxiety disorders.

Methods: This phase 3 prospective, randomized, double blind, parallel group, placebo-controlled, 15-week cohort study took place at multiple sites across India. Eligible participants were randomly assigned to one of the two treatment arms (CBD or placebo) in a 1:1 ratio.

Results: 178 participants were randomized to receive CBD (n=89) or placebo (n=89). The study met both primary (GAD-7 and HAM-A scores) and secondary outcomes (CGI-I, CGI-S, PHQ-9 and PSQI scores). The GAD-7 score difference between the end of treatment and baseline for the CBD versus the placebo was -7.02 (S.E: 0.25, 95% CI -7.52; -6.52), p<0.0001. Similarly, the HAM-A score difference at the end of treatment compared to baseline for the CBD versus the placebo was -11.9 (S.E: 0.33, 95% CI -12.6; -11.3), p<0.0001.

Conclusions: Nanodispersible CBD was therapeutically safe with no serious adverse events, well tolerated, and effective for the treatment of mild to moderate anxiety disorders, as well as associated depression and sleep quality disturbances. These results pave way for probable prospective use of nanodispersible CBD formulation for various psychiatry disorders alone or in conjunction with other drugs.”

https://pubmed.ncbi.nlm.nih.gov/38797087/

“Nanodispersible CBD oral solution was effective treating mild to moderate anxiety.”

https://www.sciencedirect.com/science/article/pii/S1876201824001667?via%3Dihub

Infant formula as a solid lipid dose form for enhancement of the oral bioavailability of cannabidiol for paediatric patients

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“Cannabinoids can save paediatric patients from harmful psychological conditions caused by epilepsy. However, the limited aqueous solubility of the drug presents a limitation to oral absorption and bioavailability.

Previous studies have shown the enhancement of oral bioavailability for poorly water-soluble drugs using milk or milk-based products like infant formula as a novel lipid-based formulation, due to digestion of the lipids to enhance drug solubility. that is particularly well suited to infants and in low economy settings.

Therefore, this study has investigated the in vitro solubilization enhancement of cannabidiol (CBD) in milk-based products during digestion using synchrotron small angle X-ray scattering, followed by pharmacokinetic studies to determine the relative oral bioavailability. The in vitro results, coupled with in vivo data, demonstrate a two-fold increase in the oral bioavailability of CBD in bovine milk as well as infant formula.

The results of this study indicate the potential for infant formula to be considered as a novel formulation approach for CBD. Further study is encouraged for more drugs with infant formula to strengthen the correlation between the solubilization of drug and their oral bioavailability.”

https://pubmed.ncbi.nlm.nih.gov/38782154/

https://www.sciencedirect.com/science/article/pii/S0378517324004915?via%3Dihub

Identification of Genes Hub Associated with Triple-Negative Breast Cancer and Cannabidiol Analogs Potential Inhibitory Agents: An In-silico Study

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“Objective: Triple-negative breast cancer presents a significant challenge in oncology due to its complex treatment and aggressive nature. This subtype lacks common cancer cell receptors like estrogen, progesterone, and human epidermal growth factor receptor 2 receptors. This study aimed to identify, through bioinformatic analysis, the key genes associated with triple-negative breast cancer. In addition, CBD analogs with potential inhibitory effects on these genes were evaluated through docking and molecular dynamics.

Methods: Gene expression profiles from the GSE178748 dataset were analyzed, focusing on MDA-MB-231 breast cancer cell lines. Differentially expressed genes were determined through protein-protein interaction networks and subsequently validated. Additionally, the inhibitory effects of cannabidiol analogs on these hub genes were assessed using molecular docking and dynamics.

Results: Analysis of the hub highlighted RPL7A, NHP2L1, and PSMD11 as significant players in TNBC regulation. Ligand 44409296 showed the best affinity energy with RPL7A, while 166505341 exhibited the highest affinity with NHP2L1 and PSMD11, surpassing CBD. Analyses of RMSD, RMSF, SASA, and Gyration Radius indicated structural stability and interactions of the proteins with ligands over time. MMGBSA calculations showed favorable binding energies for the ligands with the target proteins.

Conclusion: In conclusion, this study identified key genes, namely RPL7A, NHP2L1, and PSMD11, associated with triple-negative breast cancer and demonstrated promising interactions with cannabidiol analogs, particularly 44409296 and 166505341. These findings suggest potential therapeutic targets and highlight the relevance of further clinical investigations. Additionally, the ligands exhibited favorable ADME properties and low toxicity, underscoring their potential in future drug development for TNBC treatment.”

https://pubmed.ncbi.nlm.nih.gov/38809637/

https://journal.waocp.org/article_91159.html

Assessment of Moroccan Cannabis sativa Seed Oil: Chemical Analysis and Evaluation of Antioxidant, Toxicological, and Antinociceptive Effects

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“Cannabis sativa L. is a plant known locally as “El kif” of the Cannabaceae family. This study aimed to conduct a chemical analysis of Cannabis sativa seed oil (CSSO) and assess its acute toxicity, antioxidant properties, and analgesic effects.

The chemical analysis was performed using gas chromatography and mass spectrometry (GC/MS) to identify its fatty acids (FAs) content. Antioxidant activity was evaluated in vitro using the DPPH (2,2-diphenyl-1-picrylhydrazyl) radical scavenging method and the FRAP (ferric reducing antioxidant power) method. Concurrently, acute toxicity, along with antinociceptive activity, was studied through three distinct animal models: writhing test, formalin test, and hot plate test.

The results revealed that linoleic acid, oleic acid, α-linolenic acid, and palmitic acid were the main components of CSSO. The LD50 of CSSO was greater than 5 g/kg, indicating low toxicity. Additionally, CSSO exhibited a significant content of flavonoids and total polyphenols, along with notable antioxidant activity with values. The results indicated a significant increase in thermal stimulus latency, a reduction in the number of writhes induced by acetic acid, and a decrease in licking time in both phases of the formalin test.

In conclusion, this study suggests promising results for CSSO emphasizing its potential as a therapeutic agent.”

https://pubmed.ncbi.nlm.nih.gov/38795371/

https://onlinelibrary.wiley.com/doi/10.1002/cbdv.202400591

Cannabis Sativa Oil Promotes Social Interaction and Ultrasonic Communication by Acting on Oxytocin Pathway

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“Objective: Cannabis sativa is the most used recreational drug worldwide. In recent years, there has been a growing interest in the potential therapeutic benefits of medicinal cannabis to treat a variety of psychiatric and neurological conditions. In particular, cannabidiol (CBD), a nonpsychoactive cannabis constituent, has been investigated for its potential prosocial effects on behavior, although the molecular mechanisms underlying this effect are still largely unknown. The aim of this study was to investigate the effect of a C. sativa oil CBD rich (CS oil) on social interaction and ultrasonic communication in mice. 

Study Design: Twenty-seven adult male mice (B6; 129P F2) were treated daily with vehicle or CS oil for 2 weeks. At Day 14, mice were tested for behavior (social interaction test and ultrasonic communication). Forty minutes before the behavioral tests, mice were exposed to intranasal treatment with vehicle or the oxytocin receptor antagonist, L-371,257. After behavioral tests, VH- and CS oil-treated mice were sacrificed, RNA was extracted from the hypothalamus and used for quantitative Real Time-PCR experiments. 

Results: We found that a 2-week treatment with the CS oil on mice exerted a prosocial effect associated with an increase in ultrasonic vocalizations. These effects were inhibited by pretreating mice with an oxytocin receptor antagonist. In addition, at the molecular level, we found that CS oil treatment caused a significant increase in oxytocin and a decrease in oxytocin receptor expression levels in the brain hypothalamus. 

Conclusion: Our results suggest that CS oil promotes social behavior by acting on oxytocin pathway.”

https://pubmed.ncbi.nlm.nih.gov/38800950/

https://www.liebertpub.com/doi/10.1089/can.2024.0062

Effect of Cannabis sativa L. extracts, phytocannabinoids and their acetylated derivates on the SHSY-5Y neuroblastoma cells’ viability and caspases 3/7 activation

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“Background: There is a need for novel treatments for neuroblastoma, despite the emergence of new biological and immune treatments, since refractory pediatric neuroblastoma is still a medical challenge. Phyto cannabinoids and their hemisynthetic derivatives have shown evidence supporting their anticancer potential. The aim of this research was to examine Phytocannabinoids or hemisynthetic cannabinoids, which reduce the SHSY-5Y, neuroblastoma cell line’s viability.

Methods: Hexane and acetyl acetate extracts were produced starting with Cannabis sativa L. as raw material, then, 9-tetrahidrocannabinol, its acid counterpart and CBN were isolated. In addition, acetylated derivatives of THC and CBN were synthesized. The identification and purity of the chemicals was determined by High Performance Liquid Chromatography and 1H y 13C Magnetic Nuclear Resonance. Then, the capacity to affect the viability of SHSY-5Y, a neuroblastoma cell line, was examined using the resazurin method. Finally, to gain insight into the mechanism of action of the extracts, phytocannabinoids and acetylated derivatives on the examined cells, a caspase 3/7 determination was performed on cells exposed to these compounds.

Results: The structure and purity of the isolated compounds was demonstrated. The extracts, the phytocannabinoids and their acetylated counterparts inhibited the viability of the SHSY 5Y cells, being CBN the most potent of all the tested molecules with an inhibitory concentration of 50 percent of 9.5 µM.

Conclusion: Each of the evaluated molecules exhibited the capacity to activate caspases 3/7, indicating that at least in part, the cytotoxicity of the tested phytocannabinoids and their hemi-synthetic derivatives is mediated by apoptosis.”

https://pubmed.ncbi.nlm.nih.gov/38802872/

“Phyto cannabinoids exhibit higher viability inhibition capacity than the originating extracts. This activity is at least partially associated with an apoptosis inducing property. From all the tested molecules, CBN is a promising molecule for further studies as an anticancer agent for neuroblastoma treatment.”

https://biolres.biomedcentral.com/articles/10.1186/s40659-024-00506-0

Effectiveness, Safety and Patients’ Satisfaction of Nabiximols (Sativex®) on Multiple Sclerosis Spasticity and Related Symptoms in a Swiss Multicenter Study

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“Background: Cannabinoid oro-mucosal spray nabiximols is approved for patients with moderate to severe multiple sclerosis spasticity (MSS) resistant to other antispastic medications. Few real-world data are available on the effectiveness, safety and patients’ satisfaction in MS patients treated with nabiximols as monotherapy. 

Methods: To investigate the effectiveness, tolerability and satisfaction of nabiximols in a real-life multicentric Swiss cohort as monotherapy or with stable doses of other antispastic medications, and explore clinical features which may predict treatment response. The following data were collected at treatment start (baseline) and 12 weeks thereafter: Modified Ashworth scale (MAS), scores at numerical rating scales ranging from 0 (absent) to 10 (considerable) for effect on spasticity (sNRS), pain (pNRS), gait (gNRS), urinary symptoms (uNRS), tolerability (tNRS) as assessed by the treating neurologist, and overall treatment satisfaction (TsNRS) and tolerability (tNRS) as assessed by the patient. 

Results: Ninety-five patients (44 relapsing remitting, 37 secondary progressive and 14 primary progressive MS; median age = 53 (IQR 45-62); female 70%; median EDSS 6 (IQR 4-6), concomitant antispastic treatments in 54% of patients) were included. From baseline to week 12, median MAS score decreased from 3.0 to 2.0 (p < 0.001). Median scores of the each NRS also significantly decreased (p < 0.001 for all comparisons). At week 12, the median TsNRS and tTS scores were 8/10 (IQR: 6-9) and 9/10 (IQR: 7-10), respectively, and 93.7% of patients continued to use nabiximols at the average dose of six sprays/day. No clinical factors, including use of nabiximols as add on vs. monotherapy, were associated with responder status. 

Conclusions: Our first Swiss, multicentric, observational, real-life study supports and enhances previous finding of nabiximols as monotherapy and as add-on therapy, being an effective, safe and well-tolerated treatment option for resistant MS spasticity and spasticity-related symptoms (pain, bladder dysfunction and gait).”

https://pubmed.ncbi.nlm.nih.gov/38792448/

https://www.mdpi.com/2077-0383/13/10/2907

Marijuana Use May Be Associated with Reduced Prevalence of Prostate Cancer: A National Survey on Drug Use and Health Study from United States of America

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“Preclinical evidence indicates the potential anti-tumor capabilities of cannabinoids in prostate cancer (PC).

We undertook a cross-sectional study using National Survey on Drug Use and Health data from 2002 to 2020, involving 2503 participants in the USA. The independent variable was marijuana use status (current, former, never), while the dependent variable was self-reported PC (yes, no). Eleven other demographic variables were assessed as covariates.

PC prevalence was lower among current marijuana users (46/145, 31.7%) and former users (323/1021, 31.6%) compared to non-users (534/1337, 39.9%, p < 0.001). PC prevalence was lower among users versus non-users in the elderly (≥65) (36.4% vs. 42.4%, p = 0.016) and non-Hispanic white subgroups (28.9% vs. 38.3%, p < 0.001). There were no significant PC prevalence differences between users and non-users in the younger population (50-64) or other race/ethnicity.

In the multivariable analyses, former marijuana use was associated with lower PC compared to never using (odd ratio = 0.74, 95% CI 0.62-0.90, p = 0.001). Current use was also suggestive of reduced prevalence but was not statistically significant (odd ratio = 0.77, 95% CI 0.52-1.14, p = 0.198), possibly due to low sample size.

Our findings from a large national survey provide additional data to link marijuana use with lower PC prevalence.”

https://pubmed.ncbi.nlm.nih.gov/38790970/

https://www.mdpi.com/2227-9059/12/5/1008

Cannabis sativa (Hemp) seed-derived peptides WVYY and PSLPA modulate the Nrf2 signaling pathway in human keratinocytes

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“Cannabis sativa (Hemp) seeds are used widely for cosmetic and therapeutic applications, and contain peptides with substantial therapeutic potential.

Two key peptides, WVYY and PSLPA, extracted from hemp seed proteins were the focal points of this study. These peptides have emerged as pivotal contributors to the various biological effects of hemp seed extracts. Consistently, in the present study, the biological effects of WVYY and PSLPA were explored.

We confirmed that both WVYY and PSLPA exert antioxidant and antibacterial effects and promote wound healing.

We hypothesized the involvement of the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway in these observed effects, given that Nrf2 is reported to be a central player in the regulation of these observed effects. Molecular-level investigations unequivocally confirmed the role of the Nrf2 signaling pathway in the observed effects of WVYY and PSLPA, specifically their antioxidant effects.

Our study highlights the therapeutic potential of hemp seed-derived peptides WVYY and PSLPA, particularly with respect to their antioxidant effects, and provides a nuanced understanding of their effects. Further, our findings can facilitate the investigation of targeted therapeutic applications and also underscore the broader significance of hemp extracts in biological contexts.”

https://pubmed.ncbi.nlm.nih.gov/38781174/

“Although a more in-depth investigation into the precise roles of each peptide is necessary, we believe that a thorough examination of the highly specific roles of various peptides could lead to a broad range of medical and biological applications. In conclusion, we confirmed that the peptides WVYY and PSLPA derived from hemp seed extracts exhibit multiple effects, including antioxidant mechanisms. We propose that the overall “effect” of hemp extract originates from these contributions.”

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0298487

Evaluating the Metabolomic Profile and Anti-Pathogenic Properties of Cannabis Species

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“The Cannabis species is one of the potent ancient medicinal plants acclaimed for its medicinal properties and recreational purposes. The plant parts are used and exploited all over the world for several agricultural and industrial applications. For many years Cannabis spp. has proven to present a highly diverse metabolomic profile with a pool of bioactive metabolites used for numerous pharmacological purposes ranging from anti-inflammatory to antimicrobial. Cannabis sativa has since been an extensive subject of investigation, monopolizing the research. Hence, there are fewer studies with a comprehensive understanding of the composition of bioactive metabolites grown in different environmental conditions, especially C. indica and a few other Cannabis strains. These pharmacological properties are mostly attributed to a few phytocannabinoids and some phytochemicals such as terpenoids or essential oils which have been tested for antimicrobial properties. Many other discovered compounds are yet to be tested for antimicrobial properties. These phytochemicals have a series of useful properties including anti-insecticidal, anti-acaricidal, anti-nematicidal, anti-bacterial, anti-fungal, and anti-viral properties. Research studies have reported excellent antibacterial activity against Gram-positive and Gram-negative multidrug-resistant bacteria as well as methicillin-resistant Staphylococcus aureus (MRSA). Although there has been an extensive investigation on the antimicrobial properties of Cannabis, the antimicrobial properties of Cannabis on phytopathogens and aquatic animal pathogens, mostly those affecting fish, remain under-researched. Therefore, the current review intends to investigate the existing body of research on metabolomic profile and anti-microbial properties whilst trying to expand the scope of the properties of the Cannabis plant to benefit the health of other animal species and plant crops, particularly in agriculture.”

https://pubmed.ncbi.nlm.nih.gov/38786730/

“Cannabis extracts and their phytochemicals have so far been demonstrated to be a solution.”

https://www.mdpi.com/2218-1989/14/5/253