Cancer-Cachexia-Induced Human Skeletal Muscle Myotube Degeneration Is Prevented via Cannabinoid Receptor 2 Agonism In Vitro

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“Cachexia syndrome, leading to reduced skeletal muscle and fat mass, is highly prevalent in cancer patients, resulting in further negative implications for these patients. To date, there is no approved therapy for cachexia syndrome. The objective of this study was to establish an in vitro model of cancer cachexia in mature human skeletal muscle myotubes, with the intention of exploiting the cell model to assess potential cachexia therapeutics, specifically cannabinoid related drugs. Having cultured and differentiated primary human muscle myoblasts to mature myotubes, we successfully established two cancer cachexia models using conditioned media (CM) from human colon adenocarcinoma (SW480) and from non-small-cell lung carcinoma (H1299) cultured cells. The cancer-CM-induced extensive myotube degeneration, demonstrated by a significant reduction in mature myotube diameter, which progressed over the period studied. Myotube degeneration is a characteristic feature of cancer cachexia and was used in this study as an index of cachexia. Expression of cannabinoid 1 and 2 receptors (CB1R and CB2R) was confirmed in the mature human skeletal muscle myotubes. Subsequently, the effect of cannabinoid compounds on this myotube degeneration were assessed.

Tetrahydrocannabinol (THC), a partial CB1R/CB2R agonist, and JWH133, a selective CB2R agonist, proved efficacious in protecting mature human myotubes from the deleterious effects of both (SW480 and H1299) cancer cachexia conditions.

ART27.13, a full, peripherally selective CB1R/CB2R agonist, currently being trialled in cancer cachexia (IRAS ID 278450, REC 20/NE/0198), was also significantly protective against myotube degeneration in both (SW480 and H1299) cancer cachexia conditions. Furthermore, the addition of the CB2R antagonist AM630, but not the CB1R antagonist Rimonabant, abolished the protective effect of ART27.13. In short, we have established a convenient and robust in vitro model of cancer-induced human skeletal muscle cachexia. The data obtained using the model demonstrate the therapeutic potential of ART27.13 in cancer-induced cachexia prevention and provides evidence indicating that this effect is via CB2R, and not CB1R.”

“Several cannabinoid drugs have emerged as potential therapeutics for various conditions.”

Efficacy and safety of medical cannabinoids in children with cerebral palsy: a systematic review

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“Introduction: The increasing popularity of cannabinoids for treating numerous neurological disorders has been reported in various countries. Although it reduces tetrahydrocannabinol psychoactivity, it helps patients tolerate higher doses and complements the anti-spasmodic effects of tetrahydrocannabinol. One of the most important potential of cannabinoids are related to its potential to help children with cerebral palsy, a contributor of lifelong disability. Therefore, this systematic review aimed to assess the efficacy and safety of medical cannabinoids in children with cerebral palsy.

Methods: This review adhered to The Preferred Reporting Items for Systematic Reviews and Meta-analysis 2020 guidelines. Seven databases, namely, Scopus, PubMed, EBSCO Host, ProQuest, Google Scholar, Semantic Scholar, and JSTOR, were used to identify relevant studies. Studies examining pediatric patients with cerebral palsy and reporting the efficacy and safety of medical cannabinoids through clinical trials, observational cross-sectional studies, or cohort designs were included. The outcomes of the studies included the efficacy of medical cannabinoids administered for spasticity, motor components, pain control, sleep difficulties, adverse effects, and seizure control.

Results: Of 803 identified articles, only three met the inclusion criteria for data synthesis. One study exhibited a moderate risk-of-bias. A total of 133 respondents, mainly from Europe, were investigated. Overall effectiveness and safety were considered good. However, the results are inconsistent, especially regarding spasticity treatment variables.

Conclusion: The anti-spasticity, anti-inflammatory, and anti-seizure properties of cannabinoids might be beneficial for patients with cerebral palsy, although their effectiveness has not been widely studied. Further studies with larger sample sizes and various ethnicities are warranted.”

Elucidation of GPR55-Associated Signaling behind THC and LPI Reducing Effects on Ki67-Immunoreactive Nuclei in Patient-Derived Glioblastoma Cells

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“GPR55 is involved in many physiological and pathological processes. In cancer, GPR55 has been described to show accelerating and decelerating effects in tumor progression resulting from distinct intracellular signaling pathways. GPR55 becomes activated by LPI and various plant-derived, endogenous, and synthetic cannabinoids.

Cannabinoids such as THC exerted antitumor effects by inhibiting tumor cell proliferation or inducing apoptosis.

Besides its effects through CB1 and CB2 receptors, THC modulates cellular responses among others via GPR55. Previously, we reported a reduction in Ki67-immunoreactive nuclei of human glioblastoma cells after GPR55 activation in general by THC and in particular by LPI. In the present study, we investigated intracellular mechanisms leading to an altered number of Ki67+ nuclei after stimulation of GPR55 by LPI and THC. Pharmacological analyses revealed a strongly involved PLC-IP3 signaling and cell-type-specific differences in Gα-, Gβγ-, RhoA-ROCK, and calcineurin signaling. Furthermore, immunochemical visualization of the calcineurin-dependent transcription factor NFAT revealed an unchanged subcellular localization after THC or LPI treatment. The data underline the cell-type-specific diversity of GPR55-associated signaling pathways in coupling to intracellular G proteins. Furthermore, this diversity might determine the outcome and the individual responsiveness of tumor cells to GPR55 stimulation by cannabinoids.”

Medical cannabis for refractory cancer-related pain in a specialised clinical service: a cross-sectional study

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“Background and objectives: Cancer-related pain management in advanced stages presents a significant challenge that often requires a multidisciplinary approach. Although advancements in pharmacological and interventional therapies, a considerable number of patients still suffer from refractory pain, leading to unmet clinical needs. This study shares our experience with medical cannabis (MC) as a potential therapy for this specific population of patients with cancer-related refractory pain.

Methods: In a cross-sectional study, 252 consecutive refractory cancer-related pain patients (mean age=61.71, SD=14.02, 47.6% males) filled out detailed self-report questionnaires. Of these, 126 patients (55%) were treated with MC and 105 patients (45%) were not.

Results: Most patients received pain management from their oncologist, not a pain specialist. MC was mainly started for pain relief, sleep difficulties and anorexia. About 70% of patients reported subjective improvement from MC, with almost 40% reporting a significant improvement in coping with their illness. Side effects were generally mild, with fatigue and dizziness being the most common (21.78% and 23.46%, respectively). No patient required dedicated medical care for side effects. Of non-users, 65% had tried MC before and stopped due to lack of effectiveness or side effects (39.7% and 34.6%, respectively).

Conclusion: Refractory cancer pain necessitates innovative approaches. This registry highlights that MC can effectively improve symptoms in non-responsive patients, with favourable safety profiles for this vulnerable population.”

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.”

“Psychedelic drugs in the treatment of psychiatric disorders”

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.”

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.”

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.”

Neuro-Gastro-Cannabinology: A Novel Paradigm for Regulating Mood and Digestive Health

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“The maintenance of homeostasis in the gastrointestinal (GI) tract is ensured by the presence of the endocannabinoid system (ECS), which regulates important physiological activities, such as motility, permeability, fluid secretion, immunity, and visceral pain sensation. Beside its direct effects on the GI system, the ECS in the central nervous system indirectly regulates GI functions, such as food intake and energy balance. Mounting evidence suggests that the ECS may play an important role in modulating central neurotransmission which affects GI functioning. It has also been found that the interaction between the ECS and microbiota affects brain and gut activity in a bidirectional manner, and a number of studies demonstrate that there is a strong relationship between GI dysfunctions and mood disorders. Thus, microbiota can regulate the tone of the ECS. Conversely, changes in intestinal ECS tone may influence microbiota composition. In this mini-review, we propose the concept of neuro-gastro-cannabinology as a novel and alternative paradigm for studying and treating GI disorders that affect mood, as well as mood disorders that imbalance GI physiology. This concept suggests the use of prebiotics or probiotics for improving the tone of the ECS, as well as the use of phytocannabinoids or endocannabinoid-like molecules, such as palmitoylethanolamide, to restore the normal intestinal microbiota. This approach may be effective in ameliorating the negative effects of GI dysfunctions on mood and/or the effects of mood disorders on digestive health.”

“In particular, the use of cannabis-derived compounds that decrease the impact of stress, regulate circadian rhythm, and improve mood may represent a winning strategy in case of functional GI diseases.”

Cannabis Use Is Associated With Fewer Filled Opioid Prescriptions After Treatment of Proximal Humerus Fractures

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“The purpose of this study was to use a large claims database to determine if there is a difference in opioid use after operative intervention for proximal humerus fractures in patients with known cannabis use compared with those who do not report cannabis use. The PearlDiver database was queried to find all patients who underwent proximal humerus open reduction and internal fixation. A group of patients with reported cannabis use or dependence was matched to a cohort without known cannabis use. Between the two groups, differences in the number of opioid prescriptions filled in the postoperative period (within 3 days), the morphine milligram equivalents (MMEs) prescribed in total and per day, and the number of opioid prescription refills were explored. There were 66,445 potential control patients compared with 1260 potential study patients. After conducting the propensity score match, a total of 1245 patients were included in each group. The patients in the cannabis group filled fewer opioid prescriptions (P=.045) and were prescribed fewer total MMEs (P=.044) in the first 3 days postoperatively. Results of this study indicate that patients who use cannabis products may use fewer opioids after proximal humerus open reduction and internal fixation.”