Cannabis use, sleep and mood disturbances among persons with epilepsy – A clinical and polysomnography study from a Canadian tertiary care epilepsy center

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“Objective: Interest in anti-seizure properties of cannabinoids is increasing, with the rise in prevalence of recreational and medical cannabis use, especially across Canada. In a recent study on people with epilepsy (PWE), cannabis use showed a strong association with poor psychosocial health. Sleep and mood comorbidities are highly prevalent in epilepsy, and are common motivations for cannabis use. The primary objective of this study was to assess demographic, subjective and objectively assessed sleep quality and mood related differences among PWE who regularly use cannabis compared to those who do not.

Methods: Consecutive consenting patients with a confirmed epilepsy diagnosis, admitted to our Epilepsy Monitoring Unit, over a 3-year period (2019-2022) were enrolled. Detailed epilepsy-related data and self-reported sleep [Pittsburgh Sleep quality index (PSQI)], Epworth Sleepiness Scale (ESS)], mood [(Beck’s Depression Inventory (BDI) and Beck’s Anxiety inventory (BAI)] and cannabis use related data were collected. Overnight polysomnography (PSG) was conducted on the first night of admission, with simultaneous 18-channel video-EEG. Sleep (PSG) scoring followed American Academy of Sleep Medicine guidelines by a scorer blinded to clinical details.

Results: Among 51 patients with similar seizure control, 25 (13 F) reported cannabis use (mean age 36.3+14.8 years) and were significantly younger than 26 (18 F) non-users (mean age 48.3+15 years). Cannabis users had significantly better subjective sleep quality (mean PSQI scores 7.2+2.9 vs 10.2+5.2 respectively). Most patients endorsed sleepiness (Cannabis users with ESS scores greater than 10; 91.3 %, 77.3 % in non-users) and moderate to extreme depression (BDI) scores. No significant differences were observed in objective sleep parameters. BDI score significantly predicted PSQI and ESS scores on multiple logistic regression analysis.

Significance: Despite a significant age difference, self-reported sleep quality is better among PWE who report regular cannabis use compared to non-users. However, there is no significant difference in objective sleep quantity and quality from PSG between the two groups. Additionally, severity of depressive symptoms is a significant predictor of sleep quality and of excessive daytime sleepiness among PWE.”

https://pubmed.ncbi.nlm.nih.gov/39586190/

https://www.sciencedirect.com/science/article/pii/S0920121124001943?via%3Dihub

Patient-Reported Outcomes of Pain, Stiffness, and Fatigue Reduction in Rheumatoid and Psoriatic Arthritis With Cannabinoid Use

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“Rheumatoid arthritis (RA) and psoriatic arthritis (PsA) are autoimmune conditions that can progressively destroy joints, causing chronic, often debilitating pain, and drastically affecting the quality of life. Novel pharmaceutical remedies have recently been developed, which allow for better symptom management. However, the complex pain experienced is challenging to control fully, leading this patient population to seek alternative treatments.

Though cannabis has been legalized for medical use in most states in the United States, the safety and efficacy of its use in inflammatory arthritis have still not been satisfactorily established. We conducted a cross-sectional study on patients with RA and PsA who visited a rheumatology outpatient clinic from October 2019 to March 2020.

We conducted a brief, voluntary, and anonymous Qualtrics survey of specific questions regarding their use of cannabinoids and their forms, sources, methods, side effects, and perceived efficacy. The survey initially involved 302 eligible candidates, but only 290 patients completed it. Among them, 84.9% (n, 247) reported a diagnosis of RA, while 15.1% (n, 44) reported PsA. Demographically, 82.3% (n, 238) were female, and 17.7% (n, 52) were male, with mean ages of 57.1 years for RA and 56.2 years for PsA.

Around 16.95% (n=40) of RA and 11.63% (n=5) of PsA patients reported cannabinoid use, primarily inhaled for RA and topical/liquid for PsA.

Post-cannabis use, a significant decrease in pain scale was noted (mean difference: 2.267, p < 0.001), with improvements in stiffness, fatigue, and swelling reported. Side effects were minimal, and most patients were willing to discuss cannabinoid treatment with their physician (80.9% RA [n=199], 86.4% PsA [n=38]).

In conclusion, our study indicates that a notable portion of the patients with inflammatory arthritis including RA and PsA reported a history of use or ongoing cannabinoid use. Furthermore, the patients reported a short-term reduction of pain, fatigue, and swelling, though it is unclear if these findings are related to a placebo effect.”

https://pubmed.ncbi.nlm.nih.gov/39583459/

“In summary, our study sheds light on the self-utilization and the reported effectiveness of cannabinoids in managing symptoms associated with RA and PsA. Our data indicate that the reduction in pain was statistically significant, suggesting cannabinoids may help alleviate the pain associated with these conditions.”

https://www.cureus.com/articles/204984-patient-reported-outcomes-of-pain-stiffness-and-fatigue-reduction-in-rheumatoid-and-psoriatic-arthritis-with-cannabinoid-use#!/

Cannabidiol regulates L-carnitine and butyric acid metabolism by modulating the gut microbiota to ameliorate collagen-induced arthritis

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“Background: Rheumatoid arthritis (RA) is one of the most common autoimmune diseases, affecting multiple systems in the body. Cannabidiol (CBD) is one of the most medically valuable active ingredients in cannabis. At present, CBD has been shown to alleviate the progression of RA; however, owing to its multiple targets, the mechanism of CBD is not clear.

Methods: On the basis of the gut microbiota, we explored the mechanism by which CBD inhibits RA progression. Metagenomic and nontargeted metabolomic analyses were used to determine the changes in the intestinal ecology and plasma metabolites of collagen-induced arthritis (CIA) rats after CBD treatment.

Results: CBD reversed gut dysbiosis in CIA rats, notably altering the abundances of Allobaculum_unclassified, Allobaculum_fili, and Prevotella_unclassified. In addition, metabolomic analysis confirmed that CBD increased the contents of butyric acid and L-carnitine. Allobaculum could produce butyric acid and Prevotella could accelerate the metabolism of L-carnitine. In addition, in vitro experiments demonstrated that L-carnitine participated in the regulation of neutrophils, macrophages and RA-fibroblast-like synoviocytes (RA-FLSs), which was consistent with the synovial changes in CIA rats caused by CBD.

Conclusion: In summary, CBD increased the plasma contents of butyric acid and L-carnitine by altering the abundances of gut microbiota, thereby inhibiting inflammation in neutrophils, macrophages and RA-FLSs. Our study is the first to explain the mechanism by which CBD alleviates progression in CIA rats from the perspective of gut microbes and metabolites, providing new views into CBD mechanisms, which warrants clinical attention.”

https://pubmed.ncbi.nlm.nih.gov/39591767/

“Cannabidiol (CBD) is one of the most medically valuable active ingredients in cannabis and has various pharmacological effects, such as neuroprotective, anxiolytic, antipsychotic, antiemetic, antitumor, anti-inflammatory, and antioxidant effects.”

https://www.sciencedirect.com/science/article/abs/pii/S0944711324009267?via%3Dihub

The Use of Cannabinoids in the Treatment of Peripheral Neuropathy and Neuropathic Pain: A Systematic Review

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“Purpose: Peripheral neuropathies are commonly occurring conditions that are chronic and debilitating for patients. Established nonsurgical treatments have yielded mixed and patient-dependent results. Although cannabinoids have demonstrated efficacy as a treatment for central neuropathic pain, the therapeutic potential of cannabis-based medications for the management of peripheral neuropathic pain caused by nerve injury, trauma, and other noncompressive etiologies has yet to be definitively established. This study aims to determine whether cannabinoids are a potentially effective treatment for pain and symptoms associated with peripheral neuropathy.

Methods: A systematic search was conducted by two independent reviewers across PubMed, Cochrane, Ovid Medline, and CINAHL to identify studies in accordance with the predetermined inclusion/exclusion criteria. Information regarding study design, medication, dosage, effect on neuropathic pain, and other related outcomes was extracted. Meta-analysis of pain scores was performed for seven studies, and descriptive statistics were used to summarize other study findings as appropriate.

Results: Of the 927 studies identified, 14 randomized controlled trials were included. Thirteen of 14 studies (79%) observed a statistically significant decrease in neuropathic pain score following treatment with a cannabinoid. Meta-analysis yielded a mean difference of -0.67 [-0.89, -0.45]) on a 0-10 scale compared with placebo. Improvements in secondary outcomes such as sleep, sensory symptoms, and quality of life were observed.

Conclusions: Our analysis of the literature shows that cannabis-based medicines may be effective in treating the pain and symptoms of peripheral neuropathy. These findings suggest the applicability of cannabis-based medicines for peripheral neuropathy.”

https://pubmed.ncbi.nlm.nih.gov/39570218/

https://www.jhandsurg.org/article/S0363-5023(24)00474-X/abstract

Discovery of Ring-Annulated Analogues of Cannabidiol as Potential Anticancer Agents: Synthesis and Biological Evaluation

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“Cannabidiol (CBD) is a nonpsychoactive cannabinoid derived from Cannabis sativa and its potential therapeutic effects extend beyond its well-known antiepileptic properties. Exploring CBD and its analogues as anticancer agents has gained significant attention in recent years.

In this study, a series of novel ring-annulated analogues of CBD with oxazinyl moiety were synthesized and evaluated for their antiproliferative effect.

The analogues 4d and 4h demonstrate promising activity against breast and colorectal cancer. Furthermore, mechanistic insights revealed that the identified candidates arrest the G1 phase of the cell cycle and induce apoptosis via the mitochondrial pathway in breast cancer cell lines.

Notably, CBD ring-annulated analogues 4d or 4h exhibit enhanced solubility, better metabolic stability, and lowered cytochrome P450 (CYP) inhibition liability compared to CBD.

These multifaceted attributes highlight the potential of cannabinoid-based candidates for further preclinical development.”

https://pubmed.ncbi.nlm.nih.gov/39563806/

https://pubs.acs.org/doi/10.1021/acsmedchemlett.4c00233

Cannabidiol/cannabidiolic acid-rich hemp (Cannabis sativa L.) extract attenuates cognitive impairments and glial activations in rats exposed to chronic stress

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“Ethnopharmacological relevance: Hemp (Cannabis sativa L.) is increasingly being recognized for its medicinal properties beside utilizing it for food, oil, and textile fibers. The high level of cannabidiol (CBD) content in hemp’s flowers shows promising neuroprotective properties without causing psychotomimetic or addictive effects. Recently, products containing CBD and its precursor, cannabidiolic acid (CBDA), have been used to treat stress-related cognitive impairment. However, the therapeutic potential of hemp extract remains inadequately explored.

Aim of the study: To investigate the effect of CBD/CBDA-rich hemp extract on learning and memory, neuroendocrine alterations, and hippocampal neuropathological changes in the chronic restraint stress model.

Materials and methods: Chronic restraint stress (CRS) was induced in male Wistar rats by immobilizing them in a restrainer for 6 hours per day for 21 consecutive days. CBD/CBDA-rich hemp extract (10 and 30 mg/kg, intraperitoneal injection) was administered daily, 1 hour before restraint. After the last day of CRS, behavioral tests for cognition were conducted using the Y-maze and object recognition tests. Serum corticosterone (CORT) levels were measured by ELISA. Histopathological changes, neuronal density, and the activation of microglia and astrocytes were visualized using cresyl violet and immunohistochemical staining.

Results: A high dose of CBD/CBDA-rich hemp extract effectively ameliorated CRS-induced cognitive impairment and reversed HPA axis hyperactivity in CRS rats by reducing CORT levels and adrenal gland weight. Additionally, CBD/CBDA-rich hemp extract protected CRS-induced damage to hippocampal neurons. Further analysis showed that CBD/CBDA-rich hemp extract reduced specific markers of microglial activation (ionized calcium-binding adaptor molecule-1, Iba-1) and astrocytic structural protein (glial fibrillary acidic protein, GFAP) in CRS rats.

Conclusion: CBD/CBDA-rich hemp extracts remarkably reversed the stress-induced behavioral perturbations and hippocampal damage, suggesting its ameliorative effect on stress response.”

https://pubmed.ncbi.nlm.nih.gov/39551282/

“Cannabidiol (CBD) and cannabidiolic acid (CBDA) is the major constituent in hemp (Cannabis sativa L.) extract”

“CBD/CBDA-rich hemp extract is effective in relieving the chronic stress-induced cognitive impairment.”

https://linkinghub.elsevier.com/retrieve/pii/S0378874124014120

Cannabis Use and Age-Related Changes in Cognitive Function From Early Adulthood to Late Midlife in 5162 Danish Men

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“Introduction: Cannabis is by far the most widely used and abused drug listed on the Drug Enforcement Administration’s Schedule I, which includes drugs with a high potential for abuse. There is evidence of short-term negative effects of cannabis use on cognition, but only a limited number of studies have explored the association between cannabis use and age-related cognitive decline. The aim of the present study was to investigate the relationship between cannabis use and age-related cognitive decline from early adulthood to late midlife.

Methods: The study population consisted of 5162 men who had participated in Danish follow-up studies on cognitive aging. These studies included scores on the military intelligence test Børge Prien’s Prøve from both the conscription assessment (mean age = 20 years; p1 and p99: 18 and 26 years) and from the follow-up (mean age = 64 years; p1 and p99: 55 and 72 years) as well as extensive data on lifestyle and health from the follow-up questionnaires. The association between cannabis use and age-related cognitive decline was investigated in linear regression models.

Results: Men with a history of cannabis use had less cognitive decline from early adulthood to late midlife compared to men without a history of cannabis use. Among cannabis users, neither age of initiation of cannabis use nor frequent use was significantly associated with a greater age-related cognitive decline.

Discussion and conclusions: In a sample of more than 5000 men followed for a mean of 44 years, we found no significant harmful effects of cannabis use on age-related cognitive decline.”

https://pubmed.ncbi.nlm.nih.gov/39508467/

“In the present study, we aimed to investigate the relationship between cannabis use and age-related cognitive decline from early adulthood to late midlife. This study contributes to the sparse knowledge on this subject and aligns with most existing studies, suggesting no association between cannabis use and greater cognitive decline. More specifically, in the present study, cannabis users experienced slightly less cognitive decline compared to nonusers, and the association remained significant when controlling for potential confounders. Among cannabis users, no significant association was found with cognitive decline for either age of initiation of cannabis use or frequent cannabis use. Further studies are needed to investigate whether these findings reflect that there are no adverse effects on cognitive decline or that the effects of cannabis are temporary and disappear after a prolonged period of time.”

https://onlinelibrary.wiley.com/doi/10.1002/brb3.70136

Cannabinoid for alcohol use disorder

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“Several pieces of evidence have implicated the endocannabinoid system on dopaminergic mesolimbic brain reward, as well as the potential role of cannabinoid receptors CB1 and CB2 on modulation of reinforced properties of drug abuse and consequently to the treatment of substance use disorder, including alcoholism.

Moreover, growing evidence has been proposed that cannabis or cannabinoid compounds may be helpful to treat alcohol use disorder (AUD).

Cannabis is prevalent among individuals who also consume alcohol. While some authors reported that cannabis may be a promising candidate as a substitute medication for AUD, some studies have demonstrated that concomitant use of alcohol and cannabis may increase the risk of adverse outcomes.

Considering that advances in the legalization and decriminalization movements regarding cannabis have led to increased availability worldwide, the current chapter aims to provide evidence on the benefits and risks of combining alcohol and cannabis, as well as the potential therapeutic use of cannabinoid compounds in treating AUD.”

https://pubmed.ncbi.nlm.nih.gov/39523058/

“Growing studies have indicated that medicinal cannabis could be reasoned as a substitute therapy for alcohol, especially among individuals who are trying to reduce drinking behavior. Based on these premises, medicinal cannabis might be safer and also produce less social harms, for this reason some studies have been pointed as a good candidate for substitute medication for alcohol.”

https://www.sciencedirect.com/science/article/abs/pii/S0074774224001089?via%3Dihub

UK medical cannabis registry: A clinical outcome analysis of medical cannabis therapy in chronic pain patients with and without co-morbid sleep impairment

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“Introduction: Chronic pain (CP) affects 35.0%-51.3% of the UK population, with 67%-88% reporting sleep disturbances. Cannabis-based medicinal products (CBMPs) have shown therapeutic potential in managing CP. Evidence suggests poor sleep worsens pain perception; therefore, this study aimed to assess patient-reported outcome measures (PROMs) following CBMP treatment in CP patients with and without co-morbid sleep impairment.

Methods: A prospective cohort study of CP patients from the UK Medical Cannabis Registry was conducted. Participants were separated by baseline single-item sleep quality scale (SQS) score into sleep impaired (SQS ≤3) and unimpaired (SQS ≥4) cohorts. The primary outcome assessed changes in PROMs from baseline to 1-, 3-, 6-, and 12-months. Participants completed the following: SQS, General Anxiety Disorder-7, EQ-5D-5L, Brief Pain Inventory (BPI), and Short-Form McGill Pain Questionnaire-2. Significance was defined as p < 0.050.

Results: 1139 participants met the inclusion criteria (sleep impaired: n = 517, 45.4%; sleep unimpaired: n = 622, 54.61%). The sleep impaired cohort showed improvements in all PROMs at each follow-up (p < 0.010). The sleep unimpaired cohort showed similar results (p < 0.050), except in SQS and ED-5Q-5L: self-care and anxiety/depression scores (p > 0.050). However, the sleep impaired cohort observed greater improvements in BPI pain severity (p < 0.050) and SQS (p < 0.001) than the sleep unimpaired cohort at all follow-ups. 2817 adverse events were self-reported between both cohorts (p = 0.197).

Discussion: These findings align with literature that shows associated improvements in pain outcomes following CBMP administration. Sleep impaired individuals were more likely to experience greater pain severity improvements. However, this was not confirmed on multivariate logistic regression analysis and instead may be confounded by baseline pain severity.

Conclusion: Whilst these results show promise for the effects of CBMPs on CP, they must be examined within the limitations of the study design. These findings provide further evidence to support the design of subsequent randomized controlled trials to verify causality between CBMPs and pain outcomes.”

https://pubmed.ncbi.nlm.nih.gov/39545361/

“The results of this observational cohort study suggest an association between CBMP treatment and improvement in pain-specific and HRQoL PROMs in CP patients with and without co-morbid sleep impairment. Notably, those with co-morbid sleep impairment were associated with greater improvements in BPI pain severity, SQS, and PGIC than those without. However, this finding was not confirmed on multivariate analysis. Reported sleep quality did improve across the cohort from baseline, and when present was also associated with improvements in pain severity, suggesting that the effects of CBMPs on sleep may provide additional benefits for individuals with chronic pain beyond affecting the transmission of nociceptive signals. At the onset of treatment, however, other variables may be better prognostic markers for response to CBMP treatment, such as severe pain or anxiety at baseline. With respect to clinical significance, 44.10% report an improvement in the sleep impaired cohort at 1-months, declining to 24.56% at 12-months. Despite being limited by its observational design, the present study can be used to inform future RCTs, in addition to current clinical practice.”

https://onlinelibrary.wiley.com/doi/10.1111/papr.13438

Therapeutic potential of minor cannabinoids in psychiatric disorders: A systematic review

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“Interest in cannabinoids’ therapeutic potential in mental health is growing, supported by evidence of the involvement of the endocannabinoid system in psychiatric disorders such as anxiety, depression, and addiction.

While the major cannabinoids cannabidiol (CBD) and Δ9-tetrahydrocannabinol (Δ9-THC) have been more extensively researched, approximately 120 minor cannabinoids from the cannabis plant have been identified. Although some displayed promising pharmacological profiles, research on their application for psychiatric disorders is fragmented.

This systematic review evaluates, for the first time, both preclinical and clinical studies exploring minor cannabinoids’ therapeutic potential in psychiatric disorders. 22 preclinical studies and one clinical study were included, investigating various minor cannabinoids in substance use disorders, anxiety disorders, depressive disorders, trauma and stressor-related disorders, psychotic disorders, neurodevelopmental disorders, and eating disorders. Despite the heterogeneous results and the moderate to high risk of bias in several articles, certain compounds demonstrate promise for further investigation.

Δ8-tetrahydrocannabidivarin (Δ8-THCV) exhibited potential for nicotine addiction; Δ9-tetrahydrocannabidivarin (Δ9-THCV) for psychotic-like symptoms; cannabidiolic acid methyl ester (CBDA-ME) alleviated anxiety and depression-like symptoms, and cannabidivarin (CBDV) autism spectrum disorder-like symptoms.”

https://pubmed.ncbi.nlm.nih.gov/39541799/

https://www.sciencedirect.com/science/article/pii/S0924977X24007508?via%3Dihub