Engineering cannabidiol synergistic carbon monoxide nanocomplexes to enhance cancer therapy via excessive autophagy

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“Although carbon monoxide (CO)-based treatments have demonstrated the high cancer efficacy by promoting mitochondrial damage and core-region penetrating ability, the efficiency was often compromised by protective autophagy (mitophagy). Herein, cannabidiol (CBD) is integrated into biomimetic carbon monoxide nanocomplexes (HMPOC@M) to address this issue by inducing excessive autophagy. The biomimetic membrane not only prevents premature drugs leakage, but also prolongs blood circulation for tumor enrichment. After entering the acidic tumor microenvironment, carbon monoxide (CO) donors are stimulated by hydrogen oxide (H2O2) to disintegrate into CO and Mn2+. The comprehensive effect of CO/Mn2+ and CBD can induce ROS-mediated cell apoptosis. In addition, HMPOC@M-mediated excessive autophagy can promote cancer cell death by increasing autophagic flux via class III PI3K/BECN1 complex activation and blocking autolysosome degradation via LAMP1 downregulation. Furthermore, in vivo experiments showed that HMPOC@M+ laser strongly inhibited tumor growth and attenuated liver and lung metastases by downregulating VEGF and MMP9 proteins. This strategy may highlight the pro-death role of excessive autophagy in TNBC treatment, providing a novel yet versatile avenue to enhance the efficacy of CO treatments. Importantly, this work also indicated the applicability of CBD for triple-negative breast cancer (TNBC) therapy through excessive autophagy.”

https://pubmed.ncbi.nlm.nih.gov/37969731/

“In our points, this comprehensive strategy will open a new door for efficient triple-negative breast cancer therapy through CBD-induced excessive autophagy.”

https://www.sciencedirect.com/science/article/pii/S2211383523001648?via%3Dihub

The psychedelic effects of cannabis: A review of the literature

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“Cannabis and classic psychedelics are controlled substances with emerging evidence of efficacy in the treatment of a variety of psychiatric illnesses. Cannabis has largely not been regarded as having psychedelic effects in contemporary literature, despite many examples of historical use along with classic psychedelics to attain altered states of consciousness.

Research into the “psychedelic” effects of cannabis, and delta-9-tetrahydrocannabinol (THC) in particular, could prove helpful for assessing potential therapeutic indications and elucidating the mechanism of action of both cannabis and classic psychedelics.

This review aggregates and evaluates the literature assessing the capacity of cannabis to yield the perceptual changes, aversiveness, and mystical experiences more typically associated with classic psychedelics such as psilocybin. This review also provides a brief contrast of neuroimaging findings associated with the acute effects of cannabis and psychedelics.

The available evidence suggests that high-THC cannabis may be able to elicit psychedelic effects, but that these effects may not have been observed in recent controlled research studies due to the doses, set, and settings commonly used. Research is needed to investigate the effects of high doses of THC in the context utilized in therapeutic studies of psychedelics aimed to occasion psychedelic and/or therapeutic experiences.

If cannabis can reliably generate psychedelic experiences under these conditions, high-THC dose cannabis treatments should be explored as potential adjunctive treatments for psychiatric disorders and be considered as an active comparator in clinical trials involving traditional psychedelic medications.”

https://pubmed.ncbi.nlm.nih.gov/37947321/

https://journals.sagepub.com/doi/10.1177/02698811231209194

“Psychedelic drugs in the treatment of psychiatric disorders”

https://pubmed.ncbi.nlm.nih.gov/37615227/

Improved Post-Traumatic Stress Disorder Symptoms and Related Sleep Disturbances after Initiation of Medical Marijuana Use: Evidence from a Prospective Single Arm Pilot Study

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“Introduction: Post-traumatic stress disorder (PTSD) is a debilitating disorder experienced by a subgroup of individuals following a life-threatening trauma. Several US states have passed laws permitting the medical use of marijuana (MMJ) by individuals with PTSD, despite very little scientific indication on the appropriateness of marijuana as a therapy for PTSD. This prospective pilot study of adults with confirmed PTSD in Florida (FL) investigated whether PTSD symptoms, sleep quality, affect, and general physical and mental health/well-being improved post-initiation of MMJ treatment.

Methods: Participants, N = 15, were recruited from two MMJ clinics in Gainesville and Jacksonville, FL. To be eligible, participants had to be 18 years of age or older, not currently on MMJ, and willing to abstain from recreational marijuana, if using any, until the State Medical Cannabis Card was obtained, screen positive for PTSD. Participants were assessed at baseline (pre-MMJ initiation) and 30 and 70 days post-MMJ initiation using the Pittsburgh Sleep Quality Index (PSQI), PTSD Checklist for DSM-5 (PCL-5), Positive and Negative Affect Schedule (PANAS), PROMIS Global Health V1.2, and semi-structured marijuana and other substance use assessment.

Results: PTSD symptom severity as measured by total PCL-5 score improved significantly at 30- and 70-day follow-ups. Similarly, statistically significant reductions in nightmares were reported at 30- and 70-day follow-ups. Corresponding improvements in sleep were noticed with participants reporting increased duration of sleep hours, sleep quality, sleep efficiency, and total PSQI score. Likewise, negative affect and global mental health improved significantly at follow-up. According to the post hoc analyses, the most statistically significant changes occurred between baseline and 30-day follow-up. The exception to this pattern was nightmares, which did not show significant improvement until day 70.

Conclusion: The findings of this study highlight the potential of MMJ in improving patient outcomes for those with PTSD, particularly concerning sleep disturbances, which often do not respond to currently available treatments.”

https://pubmed.ncbi.nlm.nih.gov/37965569/

https://karger.com/mca/article/6/1/160/869732/Improved-Post-Traumatic-Stress-Disorder-Symptoms

Effects of Two Cannabidiol Oil Products on Self-Reported Stress Relief: A Quasi-Experimental Study

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“Introduction: Estimated rates of past-month cannabidiol (CBD) use in the general public are 13-26% and emerging research examines CBD as a potential adjunct treatment for several medical conditions, including stress-related disorders (e.g., depression, anxiety, and chronic pain). However, little is known about the effects of different CBD products on self-reported stress. The present study compared the effects of two delta-9-tetrahydrocannabinol (THC)-free CBD tincture products – (1) an isolate CBD oil and (2) a broad spectrum CBD oil – on self-ratings of effectiveness of the product and ability to manage stress.

Methods: This quasi-experimental study reports on a total of 374 participants who completed either a 30- or 60-day regimen. Participants were instructed to use a 1,000 mg CBD isolate product at will, and then switch over to a 1,000 mg broad spectrum product for the remainder of the regimen (i.e., next 15 or 30 days). Self-reported effectiveness of the product and its ability to help manage stress was compared between the isolate and broad spectrum products. We also examined overall impression, quality, taste, and adverse effects of each product.

Results: Overall, both products were rated to be highly effective and able to assist with stress management. Participants reported that the broad spectrum product’s effectiveness (p < 0.001) and ability to reduce stress (p < 0.001) as greater than the isolate product across both regimens. However, participants preferred the taste of the isolate product over that of the broad spectrum across regimens (p < 0.05). For the 30-day regimen, participants reported a more positive overall impression of the isolate as compared to the broad spectrum (p < 0.001); however, overall impression did not differ between the products in the 60-day regimen. There was no difference in adverse effects or quality between the products, across both regimens.

Conclusion: These results fit with prior studies suggesting anti-stress effects of CBD. Ratings were higher for the broad spectrum as compared to the isolate product, which is consistent with prior data suggesting that cannabinoids can work synergistically to maximize benefits. Nonetheless, more controlled studies are needed to explore these effects in nonclinical and clinical populations.”

https://pubmed.ncbi.nlm.nih.gov/37942294/

https://karger.com/mca/article/6/1/138/869446/Effects-of-Two-Cannabidiol-Oil-Products-on-Self

Anxiety Modulation by Cannabinoids-The Role of Stress Responses and Coping

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“Endocannabinoids were implicated in a variety of pathological conditions including anxiety and are considered promising new targets for anxiolytic drug development. The optimism concerning the potentials of this system for anxiolysis is probably justified. However, the complexity of the mechanisms affected by endocannabinoids, and discrepant findings obtained with various experimental approaches makes the interpretation of research results difficult. Here, we review the anxiety-related effects of the three main interventions used to study the endocannabinoid system: pharmacological agents active at endocannabinoid-binding sites present on both the cell membrane and in the cytoplasm, genetic manipulations targeting cannabinoid receptors, and function-enhancers represented by inhibitors of endocannabinoid degradation and transport. Binding-site ligands provide inconsistent findings probably because they activate a multitude of mechanisms concomitantly. More robust findings were obtained with genetic manipulations and particularly with function enhancers, which heighten ongoing endocannabinoid activation rather than affecting all mechanisms indiscriminately. The enhancement of ongoing activity appears to ameliorate stress-induced anxiety without consistent effects on anxiety in general. Limited evidence suggests that this effect is achieved by promoting active coping styles in critical situations. These findings suggest that the functional enhancement of endocannabinoid signaling is a promising drug development target for stress-related anxiety disorders.”

https://pubmed.ncbi.nlm.nih.gov/37958761/

“Three hypotheses have been put forward so far on the role of endocannabinoids in emotional and behavioral control.

  • The endocannabinoid system controls behavior by its interactions with the stress system (HPA-axis) and ensures normal functioning by eliminating excessive stress responses at all three levels: the hormonal, neural, and behavioral.
  • The endocannabinoid system contributes to the integration of perception and execution, by allowing this adaptation to the environment. It buffers maladaptive responses and protects against psychiatric symptoms.
  • The endocannabinoid system promotes an active coping with challenges, which confers the organism advantages in critical situations. This may be the common denominator of its anxiolytic- and antidepression-like effects.

These three hypotheses appear complementary rather than contradictory. All three suggest that the endocannabinoid system is a valid target for the treatment of psychiatric conditions associated with dysregulated affect. The task is to find the agent that achieves the goal with minimal risks.”

https://www.mdpi.com/1422-0067/24/21/15777


An In Silico Study for Expanding the Utility of Cannabidiol in Alzheimer’s Disease Therapeutic Development

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“Cannabidiol (CBD), a major non-psychoactive component of the cannabis plant, has shown therapeutic potential in Alzheimer’s disease (AD). In this study, we identified potential CBD targets associated with AD using a drug-target binding affinity prediction model and generated CBD analogs using a genetic algorithm combined with a molecular docking system. As a result, we identified six targets associated with AD: Endothelial NOS (ENOS), Myeloperoxidase (MPO), Apolipoprotein E (APOE), Amyloid-beta precursor protein (APP), Disintegrin and metalloproteinase domain-containing protein 10 (ADAM10), and Presenilin-1 (PSEN1). Furthermore, we generated CBD analogs for each target that optimize for all desired drug-likeness properties and physicochemical property filters, resulting in improved pIC50 values and docking scores compared to CBD. Molecular dynamics (MD) simulations were applied to analyze each target’s CBD and highest-scoring CBD analogs. The MD simulations revealed that the complexes of ENOS, MPO, and ADAM10 with CBD exhibited high conformational stability, and the APP and PSEN1 complexes with CBD analogs demonstrated even higher conformational stability and lower interaction energy compared to APP and PSEN1 complexes with CBD. These findings demonstrated the capable binding of the six identified targets with CBD and the enhanced binding stability achieved with the developed CBD analogs for each target.”

https://pubmed.ncbi.nlm.nih.gov/37959001/

https://www.mdpi.com/1422-0067/24/21/16013

Effectiveness of Cannabidiol to Manage Chronic Pain: A Systematic Review

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“Objectives: Cannabidiol (CBD), a component in Cannabis, is used to treat seizures, anxiety, and pain. Little is known about how effectively CBD works in managing chronic pain, a condition characterized by discomfort that persists beyond 3-6 months or beyond expected normal healing. Therefore, this systematic review aimed to synthesize evidence on the effectiveness of CBD in chronic pain management.

Design: A systematic review of literature utilizing PRISMA 2020 guidelines.

Data sources: PubMed/MEDLINE, Web of Science, CINAHL, Academic Search Complete, PsycArticles, PsycINFO, SocINDEX, and CENTRAL. The gray literature search was performed through the World Health Organization, the Centers for Disease Control and Prevention, and the European Centre for Disease Prevention and Control.

Review/analysis methods: We searched eight databases and gray literature for relevant studies until August 30, 2022. We gathered original research articles with various study designs published in English that looked at patients who used CBD to manage their chronic pain. Two authors assessed the risk of bias and certainty of evidence using the Grading of Recommendations Assessment, Development, and Evaluation approach. We used narrative synthesis to analyze the results.

Results: We included 15 studies among 1,516 identified articles. The majority of the studies indicated pain reduction ranging from 42% – 66% with CBD alone and CBD with Tetrahydrocannabinol. Three studies showed no significant improvement in reducing pain, and one had mixed findings in pain control. The included studies had various methods of measuring pain reduction, mostly through self-reporting and scales such as visual analog scales and verbal numerical scales, among others.

Conclusion: CBD may be useful in treating chronic pain. Findings should be interpreted with caution due to the small number of included studies and heterogeneity brought about by different study designs and outcome measures. More studies with robust study designs are warranted to evaluate CBD’s effectiveness in treating chronic pain.”

https://pubmed.ncbi.nlm.nih.gov/37953193/

https://www.painmanagementnursing.org/article/S1524-9042(23)00193-5/fulltext

Cannabis Use Linked to Enhanced Empathy

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Cannabis Use Linked to Enhanced Empathy

“Summary: A new study suggests regular cannabis users may have a heightened ability to understand others’ emotions. Psychological assessments coupled with brain imaging revealed that users show stronger connectivity in brain regions associated with empathy. The research, involving 136 participants, could have implications for treating social interaction deficits.

Key Facts:

  1. Regular cannabis users may have a greater empathetic understanding of others compared to non-users.
  2. Brain imaging indicates enhanced connectivity in the anterior cingulate cortex, a region related to empathy, among cannabis users.
  3. The study’s findings may inform potential treatments for social interaction deficits in various psychological conditions.”

https://neurosciencenews.com/empathy-cannabis-use-25173/

Synergistic inhibition of glioblastoma multiforme through an in-silico analysis of luteolin and ferulic acid derived from Angelica sinensis and Cannabis sativa: Advancements in computational therapeutics

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“The primary objective of this study is to uncover novel therapeutic agents for the treatment of Glioblastoma Multiforme (GBM), a highly aggressive form of brain cancer, and Alzheimer’s Disease (AD). Given the complexity and resistance associated with both conditions, the study underscores the imperative need for therapeutic alternatives that can traverse the biological intricacies inherent in both neuro-oncological and neurodegenerative disorders. To achieve this, a meticulous, target-based virtual screening was employed on an ensemble of 50 flavonoids and polyphenol derivatives primarily derived from plant sources. The screening focused predominantly on molecular targets pertinent to GBM but also evaluated the potential overlap with neural pathways involved in AD. The study utilized molecular docking and Molecular Dynamic (MD) simulation techniques to analyze the interaction of these compounds with a key biological target, protein tyrosine phosphatase receptor-type Z (PTPRZ). Out of the 50 compounds examined, 10 met our stringent criteria for binding affinity and specificity. Subsequently, the highest value of binding energy was observed for the synergistic binding of luteolin and ferulic acid with the value of -10.5 kcal/mol. Both compounds exhibited inherent neuroprotective properties and demonstrated significant potential as pathway inhibitors in GBM as well as molecular modulators in AD. Drawing upon advanced in-silico cytotoxicity predictions and sophisticated molecular modeling techniques, this study casts a spotlight on the therapeutic capabilities of polyphenols against GBM. Furthermore, our findings suggest that leveraging these compounds could catalyze a much-needed paradigm shift towards more integrative therapeutic approaches that span the breadth of both neuro-oncology and neurodegenerative diseases. The identification of cross-therapeutic potential in flavonoids and polyphenols could drastically broaden the scope of treatment modalities against both fatal diseases.”

https://pubmed.ncbi.nlm.nih.gov/37943817/

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0293666

The holistic effects of medical cannabis compared to opioids on pain experience in Finnish patients with chronic pain

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“Background: Medical cannabis (MC) is increasingly used for chronic pain, but it is unclear how it aids in pain management. Previous literature suggests that MC could holistically alter the pain experience instead of only targeting pain intensity. However, this hypothesis has not been previously systematically tested.

Method: A retrospective internet survey was used in a sample of Finnish chronic pain patients (40 MC users and 161 opioid users). The patients evaluated statements describing positive and negative phenomenological effects of the medicine. The two groups were propensity score matched to control for possible confounding factors.

Results: Exploratory factor analysis revealed three experience factors: Negative Side Effects, Positive Holistic Effects, and Positive Emotional Effects. The MC group (matched n = 39) received higher scores than the opioid group (matched n = 39) in Positive Emotional Effects with large effect size (Rank-Biserial Correlation RBC = .71, p < .001), and in Holistic Positive Effects with medium effect size (RBC = .47, p < .001), with no difference in Negative Side Effects (p = .13). MC and opioids were perceived as equally efficacious in reducing pain intensity. Ratings of individual statements were exploratively examined in a post hoc analysis.

Conclusion: MC and opioids were perceived to be equally efficacious in reducing pain intensity, but MC additionally positively affected broader pain-related factors such as emotion, functionality, and overall sense of wellbeing. This supports the hypothesis that MC alleviates pain through holistically altering the pain experience.”

https://pubmed.ncbi.nlm.nih.gov/37941019/

“The results of the present study support the hypothesis that the effects of MC on pain experience are more holistic than those of opioids. MC may alleviate pain through affecting a broad range of pain-related experience experiental factors such as relaxation, improved sleep and mood, being able not to react to the pain, as well as a sense of control. These holistic effects of MC could explain the inconsistencies in clinical trials, where focus has mainly been on pain intensity instead of broader pain phenomenology. The results highlight the importance of taking these holistic effects into account in treating patients with MC, considering them as part of the therapeutic process.”

https://jcannabisresearch.biomedcentral.com/articles/10.1186/s42238-023-00207-7