Anti-allodynic and medullary modulatory effects of a single dose of delta-9-tetrahydrocannabinol (THC) in neuropathic rats tolerant to morphine

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“Neuropathic pain (NP) is often treated with opioids, the prolonged use of which causes tolerance to their analgesic effect and can potentially cause death by overdose. The phytocannabinoid delta-9-tetrahydrocannabinol (THC) may be an effective alternative analgesic to treat NP in morphine-tolerant subjects. Male Wistar rats developed NP after spared nerve injury, and were then treated with increasing doses of THC (1, 1.5, 2, 2.5, and 5 mg/kg, intraperitoneally) which reduced mechanical allodynia at the dose of 2.5 and 5 mg/kg. Another group of NP rats were treated with morphine (5 mg/kg, twice daily for 7 days, subcutaneously), until tolerance developed, and on day 8 received a single dose of THC (2.5 mg/kg), which significantly reduced mechanical allodynia. To evaluate the modulation of THC in the descending pain pathway, in vivo electrophysiological recordings of pronociceptive ON cells and antinociceptive OFF cells in the rostroventral medulla (RVM) were recorded after intra-PAG microinjection of THC (10 μg/μl). NP rats with morphine tolerance, compared to the control one, showed a tonic reduction of the spontaneous firing rate of ON cells by 44%, but the THC was able to further decrease it (a hallmark of many analgesic drugs acting at supraspinal level). On the other hand, the firing rate, of the antinociceptive OFF cells was increased after morphine tolerance by 133%, but the THC failed to further activate it. Altogether, these findings indicate that a single dose of THC produces antiallodynic effect in individuals with NP who are tolerant to morphine, acting mostly on the ON cells of the descending pain pathways, but not on OFF cells.”

Beyond Pain Relief: A Review on Cannabidiol Potential in Medical Therapies

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“The phytocannabinoid cannabidiol (CBD) is receiving increasing attention due to its pharmacological properties. Although CBD is extracted from Cannabis sativa, it lacks the psychoactive effects of Δ9-tetrahydrocannabinol (THC) and has become an attractive compound for pharmacological uses due to its anti-inflammatory, antioxidant, anticonvulsant, and anxiolytic potential. The molecular mechanisms involved in CBD’s biological effects are not limited to its interaction with classical cannabinoid receptors, exerting anti-inflammatory or pain-relief effects. Several pieces of evidence demonstrate that CBD interacts with other receptors and cellular signaling cascades, which further support CBD’s therapeutic potential beyond pain management. In this review, we take a closer look at the molecular mechanisms of CBD and its potential therapeutic application in the context of cancer, neurodegeneration, and autoimmune diseases.”

Exosomal delivery of cannabinoids against cancer

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“Exosomes are extracellular vesicles (EVs) originating from endosomes that play a role in cellular communication. These vesicles which mimic the parental cells that release them are promising candidates for targeted drug delivery and therapeutic applications against cancer because of their favorable biocompatibility, specific targeting, low toxicity, and immunogenicity.

Currently, Delta-9-tetrahydrocannabinol (THC), cannabidiol (CBD) and other cannabinoids (e.g., CBG, THCV, CBC), are being explored for their anticancer and anti-proliferative properties. Several mechanisms, including cell cycle arrest, proliferation inhibition, activation of autophagy and apoptosis, inhibition of adhesion, metastasis, and angiogenesis have been proposed for their anticancer activity. EVs could be engineered as cannabinoid delivery systems for tumor-specificity leading to superior anticancer effects.

This review discusses current techniques for EV isolation from various sources, characterization and strategies to load them with cannabinoids. More extensively, we culminate information available on different sources of EVs that have anticancer activity, mechanism of action of cannabinoids against various wild type and resistant tumors and role of CBD in histone modifications and cancer epigenetics. We have also enumerated the role of EVs containing cannabinoids against various tumors and in chemotherapy induced neuropathic pain.”

The Cannabis sativa genetics and therapeutics relationship network: automatically associating cannabis-related genes to therapeutic properties through chemicals from cannabis literature

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“Background: Understanding the genome of Cannabis sativa holds significant scientific value due to the multi-faceted therapeutic nature of the plant. Links from cannabis gene to therapeutic property are important to establish gene targets for the optimization of specific therapeutic properties through selective breeding of cannabis strains. Our work establishes a resource for quickly obtaining a complete set of therapeutic properties and genes associated with any known cannabis chemical constituent, as well as relevant literature.

Methods: State-of-the-art natural language processing (NLP) was used to automatically extract information from many cannabis-related publications, thus producing an undirected multipartite weighted-edge paragraph co-occurrence relationship network composed of two relationship types, gene-chemical and chemical property. We also developed an interactive application to visualize sub-graphs of manageable size.

Results: Two hundred thirty-four cannabis constituent chemicals, 352 therapeutic properties, and 124 genes from the Cannabis sativa genome form a multipartite network graph which transforms 29,817 cannabis-related research documents from PubMed Central into an easy to visualize and explore network format.

Conclusion: Use of our network replaces time-consuming and labor intensive manual extraction of information from the large amount of available cannabis literature. This streamlined information retrieval process will enhance the activities of cannabis breeders, cannabis researchers, organic biochemists, pharmaceutical researchers and scientists in many other disciplines.”

Multiple Sclerosis and Use of Medical Cannabis: A Retrospective Review of a Neurology Outpatient Population

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“Background: Patients diagnosed as having multiple sclerosis (MS) experience a wide range of symptoms requiring pharmacologic management, and many do not achieve adequate symptom control. The purpose of this study was to evaluate the role of medical cannabis (MC) as part of a comprehensive treatment plan for patients with MS.

Methods: A retrospective medical record review of 141 patients with MS receiving MC for symptom management was conducted. Data were collected for up to 4 follow-up appointments after initiation of MC. Outcomes included changes in MS symptoms, medication changes, adverse events, and changes in cognition and mobility.

Results: Patients experienced extensive MS symptom improvement after initiation of MC, with alleviation of pain (72% of patients) and spasticity (48% of patients) and improvement in sleep (40% of patients) the most common. There was a significant reduction in concomitant opioid use after initiating MC as evidenced by a significant decrease in daily morphine milligram equivalents among patients prescribed opioid analgesics (P = .01). Decreases in muscle relaxant use and benzodiazepine use did not reach significance (P > .05). The most common adverse reaction to MC was fatigue (11% of patients).

Conclusions: In many patients with MS, MC was well tolerated, eased pain and spasticity, improved sleep and other symptoms, and reduced use of concomitant opioid analgesics. Prospective studies are needed to further investigate the role of MC in the treatment of patients with MS.”

Use of Medical Cannabis by Patients with Cancer: Attitudes, Knowledge, and Practice

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“Objectives: The study sought to assess factors contributing to the demand for MC among patients with cancer.

Methods: Patients applying for a permit to receive MC at a pain and palliative clinic of a university-affiliated cancer center in Israel in 2020-2021 were asked to complete self-report questionnaires assessing attitudes, knowledge, and expectations regarding MC use. Findings were compared between first-time and repeat applicants. Repeat applicants were asked to report their indications for requesting MC, patterns of use, and treatment effect.

Results: The cohort included 146 patients: 63 first-time applicants and 83 repeat applicants. First-time applicants were more likely to consult sources other than their oncologist for MC-related information (p <.01) and expressed more concern about addiction (p <.001) and side effects (p <.05). They often erroneously assumed the treatment was subsidized (p <.001). Repeat applicants were younger (p <.05) and included more smokers (p <.05) and recreational cannabis users (p <.05); 56.6% were cancer survivors and 78% used high-potency MC. Most patients believed to some degree that MC is more effective than conventional medications for symptom control, and over half thought that MC helps to cure cancer.

Conclusion: Misconceptions regarding the effectiveness of MC for symptom management and treatment may explain the motivation of patients with cancer to apply for a permit. There seems to be an association of young age, cigarette smoking, and recreational cannabis use with ongoing use of MC among cancer survivors.”

Efficacy of cannabidiol in convulsive and nonconvulsive seizure types associated with treatment-resistant epilepsies in the expanded access program

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“Cannabidiol (CBD) Expanded Access Program (EAP), initiated in 2014, provided CBD (Epidiolex®) to patients with treatment-resistant epilepsy (TRE). In the final pooled analysis of 892 patients treated through January 2019 (median exposure 694 days), CBD treatment was associated with a 46%-66% reduction in median monthly total (convulsive plus nonconvulsive) seizure frequency. CBD was well tolerated, and adverse events were consistent with previous findings. We used pooled EAP data to investigate the effectiveness of add-on CBD therapy for individual convulsive seizure types (clonic, tonic, tonic-clonic, atonic, focal to bilateral tonic-clonic) and nonconvulsive seizure types (focal with and without impaired consciousness, absence [typical and atypical], myoclonic, myoclonic-absence) and epileptic spasms. CBD treatment was associated with a reduction in the frequency of convulsive seizure types (median percentage reduction, 47%-100%) and nonconvulsive seizure types and epileptic spasms (median percentage reduction, 50%-100%) across visit intervals through 144 weeks of treatment. Approximately 50% of patients had ≥50% reduction in convulsive and nonconvulsive seizure types and epileptic spasms at nearly all intervals. These results show a favorable effect of long-term CBD use in patients with TRE who may experience various convulsive and nonconvulsive seizure types. Future controlled trials are needed to confirm these findings.”

Cannabinoids in Treating Parkinson’s Disease Symptoms: A Systematic Review of Clinical Studies

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“Background: Parkinson’s disease (PD) is a serious neurodegenerative condition impacting many individuals worldwide. There is a need for new non-invasive treatments of PD. Cannabinoids in the form of cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC) may offer utility as treatment, and our objective was hence to conduct a systematic review regarding the clinical evidence for the efficacy and safety of cannabinoids in treating PD. 

Methods: Screening, data extraction, and quality assessments were all conducted by multiple reviewers, with discrepancies resolved by consensus. 

Results: After conducting searches in 4 different databases, 673 articles were screened. Thirteen articles were deemed eligible for inclusion in this review. It was shown that cannabis, CBD, and nabilone (a synthetic form of THC) were capable of consistently improving motor symptoms more than a placebo. All treatments improved various non-motor symptoms, particularly with cannabis improving pain intensity, and CBD improving psychiatric symptoms in a dose-dependent manner. Adverse effects were usually minor, and, in the case of CBD, rare (except at very high doses). 

Conclusion: Cannabinoids have been shown to safely offer important potential in treating motor symptoms in PD and some non-motor symptoms. More large-scale randomized control trials for specific forms of cannabinoid treatments are required to determine their overall efficacy.”

Impact of Marijuana Smoking on COPD Progression in a Cohort of Middle-Aged and Older Persons

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“Background: Limited data are available regarding marijuana smoking’s impact on development or progression of chronic obstructive pulmonary disease (COPD) in middle-aged or older adults with a variable history of tobacco cigarette smoking.

Methods: We divided ever-tobacco smoking participants in the Subpopulations and Intermediate Outcomes in COPD Study (SPIROMICS) into three groups based on self-reported marijuana use: current, former or never marijuana smokers (CMS, FMS or NMS, respectively). Longitudinal data were analyzed in participants with ≥2 visits over a period of ≥52 weeks.

Measurements: We compared CMS, FMS and NMS, and those with varying amounts of lifetime marijuana use. Mixed effects linear regression models were used to analyze changes in spirometry, symptoms, health status and radiographic metrics; zero-inflated negative binomial models were used for exacerbation rates. All models were adjusted for age, sex, race, baseline tobacco smoking amount, and FEV1 %predicted.

Results: Most participants were followed for ≥4 years. Annual rates of change in FEV1, incident COPD, respiratory symptoms, health status, radiographic extent of emphysema or air trapping, and total or severe exacerbations were not different between CMS or FMS versus NMS or between those with any lifetime amount of marijuana use versus NMS.

Conclusions: Among SPIROMICS participants with or without COPD, neither former nor current marijuana smoking of any lifetime amount was associated with evidence of COPD progression or its development. Because of our study’s limitations, these findings underscore the need for further studies to better understand longer term effects of marijuana smoking in COPD.”

“Smoking cannabis doesn’t carry the same COPD risk as tobacco, study finds”

Cannabidiol and Minor Phytocannabinoids: A Preliminary Study to Assess Their Anti-Melanoma, Anti-Melanogenic, and Anti-Tyrosinase Properties

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“Currently, there is an increased interest from both scientists and consumers in the application of cannabis/hemp/phytocannabinoids in skin-related disorders. However, most previous investigations assessed the pharmacological properties of hemp extracts, cannabidiol (CBD), or tetrahydrocannabinol (THC), with very few studies focusing on minor phytocannabinoids from hemp. In this context, the current work explored the in vitro anti-melanoma, anti-melanogenic, and anti-tyrosinase effects of cannabidiol (CBD) and three minor phytocannabinoids, namely cannabigerol (CBG), cannabinol (CBN), and cannabichromene (CBC). Among the tested human malignant melanoma cells (A375, SH4, and G361), only A375 cells were highly susceptible to the 48 h treatment with the four phytocannabinoids (IC50 values between 12.02 and 25.13 μg/mL). When melanogenesis was induced in murine melanoma B16F10 cells by α-melanocyte stimulating hormone (αMSH), CBD, CBG, and CBN significantly decreased the extracellular (29.76-45.14% of αMSH+ cells) and intracellular (60.59-67.87% of αMSH+ cells) melanin content at 5 μg/mL. Lastly, CBN (50-200 μg/mL) inhibited both mushroom and murine tyrosinase, whereas CBG (50-200 μg/mL) and CBC (100-200 μg/mL) down-regulated only the mushroom tyrosinase activity; in contrast, CBD was practically inactive. The current data show that tyrosinase inhibition might not be responsible for reducing the melanin biosynthesis in α-MSH-treated B16F10 cells. By evaluating for the first time the preliminary anti-melanoma, anti-melanogenic, and anti-tyrosinase properties of CBN and CBC and confirming similar effects for CBD and CBG, this study can expand the utilization of CBD and, in particular, of minor phytocannabinoids to novel cosmeceutical products for skin care.”