Early Administration of the Phytocannabinoid Cannabidivarin Prevents the Neurobehavioral Abnormalities Associated with the Fmr1-KO Mouse Model of Fragile X Syndrome

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“Phytocannabinoids, including the non-addictive cannabis component cannabidivarin (CBDV), have been reported to hold therapeutic potential in several neurodevelopmental disorders (NDDs). Nonetheless, the therapeutic value of phytocannabinoids for treating Fragile X syndrome (FXS), a major NDD, remains unexplored. Here, we characterized the neurobehavioral effects of CBDV at doses of 20 or 100 mg/kg in the Fmr1-knockout (Fmr1-KO) mouse model of FXS using two temporally different intraperitoneal regimens: subchronic 10-day delivery during adulthood (Study 1: rescue treatment) or chronic 5-week delivery at adolescence (Study 2: preventive treatment). Behavioral tests assessing FXS-like abnormalities included anxiety, locomotor, cognitive, social and sensory alterations. Expression of inflammatory and plasticity markers was investigated in the hippocampus and prefrontal cortex. When administered during adulthood (Study 1), the effects of CBDV were marginal, rescuing at the lower dose only the acoustic hyper-responsiveness of Fmr1-KO mice and at both doses their altered hippocampal expression of neurotrophins. When administered during adolescence (Study 2), CBDV at both doses prevented the cognitive, social and acoustic alterations of adult Fmr1-KO mice and modified the expression of several inflammatory brain markers in both wild-type littermates and mutants. These findings warrant the therapeutic potential of CBDV for preventing neurobehavioral alterations associated with FXS, highlighting the relevance of its early administration.”

https://pubmed.ncbi.nlm.nih.gov/37566006/

“Overall, these data demonstrate that CBDV, when administered chronically and starting at juvenile age, holds a solid therapeutic potential for FXS as it prevented the most relevant behavioral alterations shown by Fmr1-KO mice.”

https://www.mdpi.com/2073-4409/12/15/1927

Cannabis use may attenuate neurocognitive performance deficits resulting from methamphetamine use disorder

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“Objective: Methamphetamine and cannabis are two widely used, and frequently co-used, substances with possibly opposing effects on the central nervous system. Evidence of neurocognitive deficits related to use is robust for methamphetamine and mixed for cannabis. Findings regarding their combined use are inconclusive. We aimed to compare neurocognitive performance in people with lifetime cannabis or methamphetamine use disorder diagnoses, or both, relative to people without substance use disorders.

Method: 423 (71.9% male, aged 44.6 ± 14.2 years) participants, stratified by presence or absence of lifetime methamphetamine (M-/M+) and/or cannabis (C-/C+) DSM-IV abuse/dependence, completed a comprehensive neuropsychological, substance use, and psychiatric assessment. Neurocognitive domain T-scores and impairment rates were examined using multiple linear and binomial regression, respectively, controlling for covariates that may impact cognition.

Results: Globally, M+C+ performed worse than M-C- but better than M+C-. M+C+ outperformed M+C- on measures of verbal fluency, information processing speed, learning, memory, and working memory. M-C+ did not display lower performance than M-C- globally or on any domain measures, and M-C+ even performed better than M-C- on measures of learning, memory, and working memory.

Conclusions: Our findings are consistent with prior work showing that methamphetamine use confers risk for worse neurocognitive outcomes, and that cannabis use does not appear to exacerbate and may even reduce this risk. People with a history of cannabis use disorders performed similarly to our nonsubstance using comparison group and outperformed them in some domains. These findings warrant further investigation as to whether cannabis use may ameliorate methamphetamine neurotoxicity.”

https://pubmed.ncbi.nlm.nih.gov/37553288/

https://www.cambridge.org/core/journals/journal-of-the-international-neuropsychological-society/article/abs/cannabis-use-may-attenuate-neurocognitive-performance-deficits-resulting-from-methamphetamine-use-disorder/8AC3E796BDBD8E387D685EB892C63244

Cannabidiol-induced crosstalk of apoptosis and macroautophagy in colorectal cancer cells involves p53 and Hsp70

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“Although it has been established that cannabidiol (CBD), the major non-psychoactive constituent of cannabis, exerts antitumoral activities, the exact mechanism(s) via which tumor cells are killed by CBD are not well understood.

This study provides new insights into the potential mechanisms of CBD-induced mutual antagonism of apoptosis and macroautophagy using wild type (HCT116 p53wt, LS174T p53wt), knockout (HCT116 p53-/-) and mutant (SW480 p53mut) human colorectal cancer cells (CRC).

CBD causes a more pronounced loss in the viability of p53wt cells than p53-/- and p53mut cells, and a 5-week treatment with CBD reduced the volume of HCT116 p53wt xenografts in mice, but had no effect on the volume of HCT116 p53-/- tumors.

Mechanistically, we demonstrate that CBD only significantly elevates ROS production in cells harboring wild-type p53 (HCT116, LS174T) and that this is associated with an accumulation of PARP1. CBD-induced elevated ROS levels trigger G0/G1 cell cycle arrest, a reduction in CDK2, a p53-dependent caspase-8/9/3 activation and macroautophagy in p53wt cells. The ROS-induced macroautophagy which promotes the activation of keap1/Nrf2 pathway might be positively regulated by p53wt, since inhibition of p53 by pifithrin-α further attenuates autophagy after CBD treatment.

Interestingly, an inhibition of heat shock protein 70 (Hsp70) expression significantly enhances caspase-3 mediated programmed cell death in p53wt cells, whereas autophagy-which is associated with a nuclear translocation of Nrf2-was blocked.

Taken together, our results demonstrate an intricate interplay between apoptosis and macroautophagy in CBD-treated colorectal cancer cells, which is regulated by the complex interactions of p53wt and Hsp70.”

https://pubmed.ncbi.nlm.nih.gov/37542074/

https://www.nature.com/articles/s41420-023-01578-9

CBD-oil as a potential solution in case of severe tamoxifen-related side effects

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“Tamoxifen may lead to bothersome side effects contributing to non-compliance and decreased quality of life.

Patients searching for relief are increasingly turning to cannabinoids such as CBD-oil. However, CBD-oil might affect tamoxifen pharmacokinetics (PK) through CYP2D6 inhibition. The aims of this open-label, single-arm study were (1) to determine the PK profile of tamoxifen when using CBD-oil, and (2) to subsequently investigate whether CBD-oil has a beneficial influence on side effects.

Study patients had to have steady-state endoxifen concentrations ≥16 nM (conservative threshold). PK sampling and side effect assessment was done at initiation of CBD-oil and 28 days thereafter. Bio-equivalence could be concluded if the 90% confidence interval (CI) for the difference in endoxifen AUC fell within the [-20%; +25%] interval. The effect of CBD-oil on side effects was evaluated using the FACT-ES questionnaire.

Endoxifen AUC decreased after CBD-oil by 12.6% (n = 15, 90% CI -18.7%, -6.1%) but remained within bio-equivalence boundaries. The endocrine sub-scale of the FACT-ES improved clinically relevant with 6.7 points (n = 26, p < 0.001) and health-related quality of life improved with 4.7 points after using CBD (95% CI + 1.8, +7.6).

We conclude that CBD-oil, if of good quality and with a dosage below 50 mg, does not have to be discouraged in patients using it for tamoxifen-related side effects.”

https://pubmed.ncbi.nlm.nih.gov/37543688/

“In conclusion, endoxifen levels remained within bio-equivalence boundaries when CBD-oil was used in combination with tamoxifen. Therefore, sublingual CBD-oil, if of good quality and not higher than the highest over-the-counter dose (<50 mg per day), does not have to be discouraged in patients using it as complementary medication. In addition, the use of CBD-oil in this single arm study resulted in a promising improvement in endocrine symptoms and quality of life, but the real effect of CBD-oil has yet to be proven in a placebo-controlled study that is currently being set up.”

https://www.nature.com/articles/s41523-023-00570-x

Dramatic efficacy of cannabidiol on refractory chronic pain in an adolescent with sickle cell disease

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“Here, we report a dramatic efficacy of cannabidiol in an adolescent with SCD suffering from chronic pain refractory to other analgesics, with complete regression of chronic pain and rapid plasma histamine level normalization after treatment.”

https://pubmed.ncbi.nlm.nih.gov/37540761/

“In conclusion, we report here for the first time a case of refractory chronic pain with dramatic improvement after CBD treatment in an adolescent with SCD. The CBD oral solution Epidiolex has been approved by the US Food and Drug Administration since June 2018 and by the European Medicine Agency since January 2023 for management of refractory epilepsy. As it seems to be a well-tolerated drug, CBD could represent a promising therapeutic perspective for patients with SCD suffering from chronic pain.”

https://onlinelibrary.wiley.com/doi/10.1002/ajh.27049

Therapeutic effect of cannabidiol on myocardial arachidonic acid content in various lipid fractions in a rat model of obesity

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“The study explored the potential protective influence of cannabidiol (CBD) on myocardial inflammation state, with a special focus on arachidonic acid (AA), and oxidative balance in lipid overload conditions.

The 7-week experiment was conducted on male Wistar rats receiving standard or high-fat diet (HFD) with intraperitoneal CBD injections for the last 14 days. The n-3 and n-6 polyunsaturated fatty acids (PUFAs) activities and AA concentration in selected fractions were evaluated by gas-liquid chromatography (GLC). The expression of proteins was determined by Western blot and the concentration of different parameters by ELISA, colorimetric, or multiplex assay kits.

Our results revealed that CBD increased n-3 PUFAs activity in phospholipid and triacylglycerol fractions, and decreased AA content in the HFD group, especially in the phospholipid pool. Simultaneously, CBD decreased the expression of nuclear factor kappa B, cyclooxygenase-1, and -2, resulting in the reduction of prostaglandin E2 and the increment of prostaglandin I2.

CBD appears to be relatively safe for the treatment of obesity-induced heart disease, as it has anti-inflammatory and partially antioxidative properties.”

https://pubmed.ncbi.nlm.nih.gov/37541613/

https://www.sciencedirect.com/science/article/abs/pii/S1098882323000643?via%3Dihub

Cannabis use for exercise recovery in trained individuals: a survey study

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“Background: Cannabis use, be it either cannabidiol (CBD) use and/or delta-9-tetrahydrocannabinol (THC) use, shows promise to enhance exercise recovery. The present study aimed to determine if individuals are using CBD and/or THC as a means of recovery from aerobic and/or resistance exercise, as well as additional modalities that might be used to aid in recovery.

Methods: Following consent, 111 participants (Mean ± SD: Age: 31 ± 13 years) completed an anonymous survey. All participants were regularly using cannabis (CBD and/or THC) as well as were currently exercising. Questions pertained to level of cannabis use, methods used for consumption of cannabis, exercise habits, exercise recovery strategies, and demographics.

Results: Eighty-five percent of participants reported participating in aerobic training. In addition, 85% of participants also reported regular participation in resistance exercise. Seventy-two percent of participants participated in both aerobic and resistance exercise. Ninety-three percent of participants felt that CBD use assisted them with recovery from exercise, while 87% of participants felt the same regarding THC use.

Conclusions: Individuals who habitually use cannabis, CBD or THC, and regularly engage in exercise do feel that cannabis assists them with exercise recovery. More data are necessary to understand the role of cannabis in exercise recovery as well as perceived ergogenic benefits of cannabis by individuals who both regularly participate in exercise and habitually use cannabis.”

https://pubmed.ncbi.nlm.nih.gov/37542349/

“CBD or THC use have been suggested to play a role in pain management, inflammation, and sleep, which are hallmarks for recovery from exercise. While data are lacking, it is clear that individuals are using cannabis and believe cannabis to have a positive effect on recovery from exercise. The present study demonstrated that in addition to more traditional recovery methods, cannabis is used as an ergogenic recovery aid by individuals that exercise regularly.”

https://jcannabisresearch.biomedcentral.com/articles/10.1186/s42238-023-00198-5

Hippocampal differential expression underlying the neuroprotective effect of delta-9-tetrahydrocannabinol microdose on old mice

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“Delta-9-tetrahydrocannabinol (THC) is the primary psychoactive compound of the cannabis plant and an exogenous ligand of the endocannabinoid system. In previous studies, we demonstrated that a single microdose of THC (0.002 mg/kg, 3-4 orders of magnitude lower than the standard dose for rodents) exerts distinct, long-term neuroprotection in model mice subjected to acute neurological insults. When administered to old, healthy mice, the THC microdose induced remarkable long-lasting (weeks) improvement in a wide range of cognitive functions, including significant morphological and biochemical brain alterations. To elucidate the mechanisms underlying these effects, we analyzed the gene expression of hippocampal samples from the model mice. Samples taken 5 days after THC treatment showed significant differential expression of genes associated with neurogenesis and brain development. In samples taken 5 weeks after treatment, the transcriptional signature was shifted to that of neuronal differentiation and survival. This study demonstrated the use of hippocampal transcriptome profiling in uncovering the molecular basis of the atypical, anti-aging effects of THC microdose treatment in old mice.”

https://pubmed.ncbi.nlm.nih.gov/37534036/

“Our findings imply that the THC microdose treatment alleviates age-dependent cognitive deficits by modulating multiple hallmarks of brain aging, supporting past hypotheses regarding the relation between aging and the endocannabinoid system.”

https://www.frontiersin.org/articles/10.3389/fnins.2023.1182932/full

Molecular pathway and structural mechanism of human oncochannel TRPV6 inhibition by the phytocannabinoid tetrahydrocannabivarin

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“The calcium-selective oncochannel TRPV6 is an important driver of cell proliferation in human cancers. Despite increasing interest of pharmacological research in developing synthetic inhibitors of TRPV6, natural compounds acting at this channel have been largely neglected. On the other hand, pharmacokinetics of natural small-molecule antagonists optimized by nature throughout evolution endows these compounds with a medicinal potential to serve as potent and safe next-generation anti-cancer drugs. Here we report the structure of human TRPV6 in complex with tetrahydrocannabivarin (THCV), a natural cannabinoid inhibitor extracted from Cannabis sativa. We use cryo-electron microscopy combined with electrophysiology, calcium imaging, mutagenesis, and molecular dynamics simulations to identify THCV binding sites in the portals that connect the membrane environment surrounding the protein to the central cavity of the channel pore and to characterize the allosteric mechanism of TRPV6 inhibition. We also propose the molecular pathway taken by THCV to reach its binding site. Our study provides a foundation for the development of new TRPV6-targeting drugs.”

https://pubmed.ncbi.nlm.nih.gov/37532722/

https://www.nature.com/articles/s41467-023-40362-2

The Effectiveness and Adverse Events of Cannabidiol and Tetrahydrocannabinol Used in the Treatment of Anxiety Disorders in a PTSD Subpopulation: An Interim Analysis of an Observational Study

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“Background: Anxiety is a condition for which current treatments are often limited by adverse events (AEs). Components of medicinal cannabis, cannabidiol (CBD) and tetrahydrocannabinol (THC), have been proposed as potential treatments for anxiety disorders, specifically posttraumatic stress disorder (PTSD). 

Objective: To evaluate quality-of-life outcomes after treatment with various cannabis formulations to determine the effectiveness and associated AEs. 

Methods: An interim analysis of data collected between September 2018 and June 2021 from the CA Clinics Observational Study. Patient-Reported Outcomes Measurement Information System-29 survey scores of 198 participants with an anxiety disorder were compared at baseline and after treatment with medicinal cannabis. The data of 568 anxiety participants were also analyzed to examine the AEs they experienced by the Medical Dictionary for Regulatory Activities organ system class. 

Results: The median doses taken were 50.0 mg/day for CBD and 4.4 mg/day for THC. The total participant sample reported significantly improved anxiety, depression, fatigue, and ability to take part in social roles and activities. Those who were diagnosed with PTSD (n = 57) reported significantly improved anxiety, depression, fatigue, and social abilities. The most common AEs reported across the whole participant cohort were dry mouth (32.6%), somnolence (31.3%), and fatigue (18.5%), but incidence varied with different cannabis formulations. The inclusion of THC in a formulation was significantly associated with experiencing gastrointestinal AEs; specifically dry mouth and nausea. 

Conclusions: Formulations of cannabis significantly improved anxiety, depression, fatigue, and the ability to participate in social activities in participants with anxiety disorders. The AEs experienced by participants are consistent with those in other studies.”

https://pubmed.ncbi.nlm.nih.gov/37529155/

https://journals.sagepub.com/doi/10.1177/87551225231180796