Cannabidiol Exerts Sedative and Hypnotic Effects in Normal and Insomnia Model Mice Through Activation of 5-HT1A Receptor

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“Cannabis sativa has been used for improving sleep for long history. Cannabidiol (CBD) has drown much attention as a non-addictive psychoactive component in Cannabis sativa extract. However, the effects of CBD on sleep architecture and it’s acting mechanism remains unclear. In the present study, we evaluated the sedative-hypnotic effect of cannabidiol (CBD), assessed the effects of CBD on sleep using a wireless physiological telemetry system. We further explored the therapeutic effects of CBD using 4-chloro-dl-phenylalanine (PCPA) induced insomnia model and changes in sleep latency, sleep duration and intestinal flora were evaluated. CBD shortened sleep latency and increases sleep duration in both normal and insomnia mice, and those effects were blocked by 5-HT1A receptor antagonist WAY100635. We determined that CBD increases 5-HT1A receptors expression and 5-HT content in the hypothalamus of PCPA-pretreated mice and affects tryptophan metabolism in the intestinal flora. These results showed that activation of 5-HT1A receptors is one of the potential mechanisms underlying the sedative-hypnotic effect of CBD. This study validated the effects of CBD on sleep and evaluated its potential therapeutic effects on insomnia.”

https://pubmed.ncbi.nlm.nih.gov/38296858/

https://link.springer.com/article/10.1007/s11064-024-04102-2

An observational study of clinical outcome measures in patients treated with cannabis-based medicinal products on the UK Medical Cannabis Registry

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“Introduction: While there is increasing evidence of the effects of cannabis-based medicinal products (CBMPs) on health-related quality of life (HRQoL), a major limitation of the current literature is the heterogeneity of studied CBMPs. This study aims to analyze changes in HRQoL in patients prescribed a homogenous selection of CBMPs.

Methods: Primary outcomes were changes in patient-reported outcomes (PROMs) at 1, 3, 6, and 12 months from baseline. The secondary outcome was an adverse events analysis. Statistical significance was defined as p < 0.050.

Results: 1378 patients prescribed Adven® CBMPs (Curaleaf International, Guernsey, UK) were included in the final analysis. 581 (42.16%) participants were current users of cannabis at baseline. 641 (46.51%), 235 (17.05%), and 502 (36.43%) patients were treated with oils, dried flowers, or a combination of the two, respectively. Improvements were found in all PROMs in each route of administration at 1, 3, 6, and 12 months from baseline (p < 0.010). Those prescribed dried flower only or both oils and dried flower experienced greater improvements in GAD-7, SQS, and EQ-5D-5L index values at 12 months (p < 0.050). There was no difference in outcomes between those prescribed dried flower only or dried flower with oils (p > 0.050). 3663 (265.82%) adverse events were reported by 297 (21.55%) patients.

Conclusion: There was an associated improvement in self-reported anxiety, sleep quality, and HRQoL in patients treated with the CBMPs. Those prescribed treatment formulations including dried flower were most likely to show a clinical improvement. However, these results must be interpreted with caution given the limitations of study design.”

https://pubmed.ncbi.nlm.nih.gov/38057993/

“In conclusion, the CBMPs studied in this analysis were associated with an improvement in self-reported anxiety, sleep quality, and HRQoL, consistent with existing literature on CBMPs. Patients prescribed treatment formulations, including dried flowers, were most likely to show clinical improvement”

https://onlinelibrary.wiley.com/doi/10.1002/npr2.12403

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

Eight Weeks of Daily Cannabidiol Supplementation Improves Sleep Quality and Immune Cell Cytotoxicity

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“Background: The endocannabinoid system is active in nervous and immune cells and involves the expression of two cannabinoid receptor genes (CB1 and CB2), along with endogenous endocannabinoid ligands, 2-arachidonoyl glycerol (2-AG) and arachidonoyl ethanolamide (anandamide), and their synthetic enzymes. Cannabidiol (CBD) is a non-intoxicating exogenous cannabinoid agonist derived from plants that, at high doses, has received FDA approval as an anticonvulsant for epileptic seizures, and at low doses is marketed as a food-grade supplement for improved mental health, sleep quality, and immunological function. At present, the predominance of published CBD clinical research has focused on ameliorative or disease-specific intervention, with few trials investigating CBD effects in healthy populations.

Methods: This clinical study aimed to investigate the effects of 8 weeks of 50 mg oral CBD on mental health, sleep quantity and quality, and immune cell function in healthy, college-aged individuals. Twenty-eight participants (average age 25.9 ± 6.1 y) were randomized to receive either daily oral capsules of 50 mg of CBD (CB, n = 14) or a calorie-matched placebo (CN, n = 14). Participants completed pre- and post-intervention assessments, including anthropometric measurements, mental health surveys, sleep analysis, and immunological function assessments.

Results: After completing the 8-week intervention, there were no significant changes in body weight and BMI (CN: 1.09 ± 0.89%: CB: 1.41 ± 1.07%), or body fat percentage (CN: 9.01 ± 7.51%: CB: 8.57 ± 7.81%), respectively (values are % change pre to post, p > 0.05). There were also no significant differences between CB and CN groups with respect to mental health measures, sleep quantity, or circulating immunophenotype as a result of the intervention. However, the CB group experienced significant improvements in sleep quality measured objectively using a sleep questionnaire (p = 0.0023) and enhanced Natural Killer (NK) immune cell function assessed in situ (p = 0.0125).

Conclusions: Eight weeks of daily 50 mg CBD may improve sleep quality, and NK immunosurveillance in healthy, younger adults.”

https://pubmed.ncbi.nlm.nih.gov/37836465/

“These results collectively support the notion that low dose CBD supplementation may offer benefits in enhancing sleep quality in humans and improving immunosurveillance against cancer cells in situ.”

https://www.mdpi.com/2072-6643/15/19/4173

A double-blind, randomized, placebo-controlled study of the safety and effects of CBN with and without CBD on sleep quality

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“The present study sought to determine the effects of cannabinol (CBN) alone and in combination with cannabidiol (CBD) on sleep quality. This was a double-blind, randomized, placebo-controlled study conducted between May and November 2022. Participants were randomized to receive either (a) placebo, (b) 20 mg CBN, (c) 20 mg CBN + 10 mg CBD, (d) 20 mg CBN + 20 mg CBD, or (e) 20 mg CBN + 100 mg CBD for seven consecutive nights. Participants were 18-55 years of age who self-rated sleep quality as “very poor” or “poor.” The primary endpoint was sleep quality, while secondary endpoints included sleep onset latency, number of awakenings, wake after sleep onset (WASO), overall sleep disturbance, and daytime fatigue. In a modified intent-to-treat analyses (N = 293), compared to placebo, 20 mg CBN demonstrated a nonsignificant but potentially meaningful effect on sleep quality (OR [95% CI] = 2.26 [0.93, 5.52], p = .082) and significantly reduced number of awakenings (95% CI [-0.96, -0.05], p = .025) and overall sleep disturbance (95% CI [-2.59, -0.14], p = .023). There was no difference from placebo among any group for sleep onset latency, WASO, or daytime fatigue (all p > .05). Individuals receiving 20 mg CBN demonstrated reduced nighttime awakenings and overall sleep disturbance relative to placebo, with no impact on daytime fatigue. The addition of CBD did not positively augment CBN treatment effects. No differences were observed for latency to sleep onset or WASO. Findings suggest 20 mg of CBN taken nightly may be helpful for improving overall sleep disturbance, including the number of times one wakes up throughout the night, without impacting daytime fatigue.”

https://pubmed.ncbi.nlm.nih.gov/37796540/

“Cannabinol (CBN), a partial agonist at cannabinoid receptor Type 1 (CB1) that is formed through the oxidation of delta-9-tetrahydrocannabinol (THC), has both alone and in combination with cannabidiol (CBD) garnered increased attention as a potential pharmacological intervention for sleep difficulties.”

https://psycnet.apa.org/fulltext/2024-14146-001.html

The therapeutic potential of purified cannabidiol

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“The use of cannabidiol (CBD) for therapeutic purposes is receiving considerable attention, with speculation that CBD can be useful in a wide range of conditions. Only one product, a purified form of plant-derived CBD in solution (Epidiolex), is approved for the treatment of seizures in patients with Lennox-Gastaut syndrome, Dravet syndrome, or tuberous sclerosis complex. Appraisal of the therapeutic evidence base for CBD is complicated by the fact that CBD products sometimes have additional phytochemicals (like tetrahydrocannabinol (THC)) present, which can make the identification of the active pharmaceutical ingredient (API) in positive studies difficult. The aim of the present review is to critically review clinical studies using purified CBD products only, in order to establish the upcoming indications for which purified CBD might be beneficial.

The areas in which there is the most clinical evidence to support the use of CBD are in the treatment of anxiety (positive data in 7 uncontrolled studies and 17 randomised controlled trials (RCTs)), psychosis and schizophrenia (positive data in 1 uncontrolled study and 8 RCTs), PTSD (positive data in 2 uncontrolled studies and 4 RCTs) and substance abuse (positive data in 2 uncontrolled studies and 3 RCTs). Seven uncontrolled studies support the use of CBD to improve sleep quality, but this has only been verified in one small RCT. Limited evidence supports the use of CBD for the treatment of Parkinson’s (3 positive uncontrolled studies and 2 positive RCTs), autism (3 positive RCTs), smoking cessation (2 positive RCTs), graft-versus-host disease and intestinal permeability (1 positive RCT each). Current RCT evidence does not support the use of purified oral CBD in pain (at least as an acute analgesic) or for the treatment of COVID symptoms, cancer, Huntington’s or type 2 diabetes.

In conclusion, published clinical evidence does support the use of purified CBD in multiple indications beyond epilepsy. However, the evidence base is limited by the number of trials only investigating the acute effects of CBD, testing CBD in healthy volunteers, or in very small patient numbers. Large confirmatory phase 3 trials are required in all indications.”

https://pubmed.ncbi.nlm.nih.gov/37312194/

https://jcannabisresearch.biomedcentral.com/articles/10.1186/s42238-023-00186-9

A Retrospective Medical Record Review of Adults with Non-Cancer Diagnoses Prescribed Medicinal Cannabis

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“Research describing patients using medicinal cannabis and its effectiveness is lacking. We aimed to describe adults with non-cancer diagnoses who are prescribed medicinal cannabis via a retrospective medical record review and assess its effectiveness and safety. From 157 Australian records, most were female (63.7%; mean age 63.0 years). Most patients had neurological (58.0%) or musculoskeletal (24.8%) conditions. Medicinal cannabis was perceived beneficial by 53.5% of patients.

Mixed-effects modelling and post hoc multiple comparisons analysis showed significant changes overtime for pain, bowel problems, fatigue, difficulty sleeping, mood, quality of life (all p < 0.0001), breathing problems (p = 0.0035), and appetite (p = 0.0465) Symptom Assessment Scale scores. For the conditions, neuropathic pain/peripheral neuropathy had the highest rate of perceived benefit (66.6%), followed by Parkinson’s disease (60.9%), multiple sclerosis (60.0%), migraine (43.8%), chronic pain syndrome (42.1%), and spondylosis (40.0%). For the indications, medicinal cannabis had the greatest perceived effect on sleep (80.0%), followed by pain (51.5%), and muscle spasm (50%). Oral oil preparations of balanced delta-9-tetrahydrocannabinol/cannabidiol (average post-titration dose of 16.9 mg and 34.8 mg per day, respectively) were mainly prescribed. Somnolence was the most frequently reported side effect (21%).

This study supports medicinal cannabis’ potential to safely treat non-cancer chronic conditions and indications.”

“Cannabis (Cannabaceae) has been used medicinally since 400 AD for its analgesic, appetite enhancement, and myorelaxant properties. Emerging evidence suggests that people with chronic conditions may benefit from using medicinal cannabis for treating chronic pain, multiple sclerosis-related spasticity, epilepsy, Parkinson’s disease, insomnia, and anxiety.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9965412/

Evaluating the impact of cannabinoids on sleep health and pain in patients with chronic neuropathic pain: a systematic review and meta-analysis of randomized controlled trials

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“Background: Chronic neuropathic pain is often debilitating and can have a significant impact on sleep health and quality of life. There is limited information on the impact of cannabinoids on sleep health when treating neuropathic pain.

Objective: The objectives of this systematic review and meta-analysis were to determine the effect of cannabinoids on sleep quality, pain intensity, and patient impression of treatment efficacy in patients with neuropathic pain.

Evidence review: Nine available medical literature databases were searched for randomized controlled trials comparing synthetic and natural cannabinoids to placebo in patients with neuropathic pain syndromes. Data on validated tools for sleep quality, pain intensity, patients’ global impression of change (PGIC), and incidence of adverse effects of cannabinoids were extracted and synthesized.

Findings: Of the 3491 studies screened, eight randomized controlled trials satisfied the inclusion criteria for this review. Analyses were performed using R -4.1.2. using the metafor package and are interpreted using alpha=0.05 as the threshold for statistical significance. Validated measures for sleep health were not used in most studies. Meta-analysis of data from six studies showed that cannabinoids were associated with a significant improvement in sleep quality (standardized mean difference (SMD): 0.40; 95% CI: 0.19 to -0.61, 95% prediction interval (PI): -0.12 to 0.88, p-value=0.002, I2=55.26, τ2=0.05, Q-statistic=16.72, GRADE: moderate certainty). Meta-analysis of data from eight studies showed a significant reduction in daily pain scores in the cannabinoid (CB) group (SMD: -0.55, 95% CI:-0.69 to -0.19, 95% PI: -1.51 to 0.39, p=0.003, I2=82.49, τ2=0.20, Q-statistic=47.69, GRADE: moderate certainty). However, sleep health and analgesic benefits were associated with a higher likelihood of experiencing daytime somnolence, nausea, and dizziness.

Conclusions: Cannabinoids have a role in treating chronic neuropathic pain as evidenced by significant improvements in sleep quality, pain intensity, and PGIC. More research is needed to comprehensively evaluate the impact of cannabinoids on sleep health and analgesic efficacy.”

https://pubmed.ncbi.nlm.nih.gov/36598058/

https://rapm.bmj.com/content/early/2022/12/04/rapm-2021-103431

Medicinal cannabis improves sleep in adults with insomnia: a randomised double-blind placebo-controlled crossover study

“Insomnia or difficulty falling and or staying asleep is experienced by up to 30% of the general population.

This randomised crossover double-blind placebo-controlled 6-week trial aimed to assess the tolerability and effectiveness of the Entoura-10:15 medicinal cannabis oil on sleep in adults with insomnia. A total of 29 participants with self-reported clinical insomnia completed the crossover trial. Participants were randomly allocated to receive placebo or active oil containing 10 mg/ml tetrahydrocannabinol (THC) and 15 mg/ml cannabidiol (CBD) over 2-weeks titrated 0.2-1.5 ml/day, followed by a 1-week wash-out period before crossover. Tolerability was assessed by daily diary. Effectiveness was measured by saliva midnight melatonin levels, validated questionnaires, i.e., the Insomnia Severity Index, and the Fitbit activity/sleep wrist tracker.

Entoura-10:15 medicinal cannabis oil was generally well tolerated, and was effective in improving sleep, whereby 60% of participants no longer classified as clinical insomniacs at the end of the 2-week intervention period. Midnight melatonin levels significantly improved in the active group by 30% compared to a 20% decline in the placebo group (p = 0.035). Medicinal cannabis oil improved both time and quality of sleep, in particular light sleep increased by 21 min/night compared to placebo (p = 0.041). The quality of sleep improved overall by up to 80% in the active group (pPhase2 = 0.003), including higher daily functioning (p = 0.032). Observed effects were more pronounced in Phase 2 due to the period effect and loss of blinding.

Entoura-10:15 medicinal cannabis oil was well tolerated and effective in improving sleep in adults with insomnia.”

https://pubmed.ncbi.nlm.nih.gov/36539991/

“In summary, our short-term trial suggests Entoura 10:15 medicinal cannabis oil, containing THC:CBD 10:15 and lesser amounts of other CBs and naturally occurring terpenes, to be well tolerated and effective in significantly improving sleep quality and duration, midnight melatonin levels, quality of life, and mood within 2-weeks in adults with insomnia.”

https://onlinelibrary.wiley.com/doi/10.1111/jsr.13793

Use of Cannabidiol in the Management of Insomnia: A Systematic Review

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“Background: Cannabidiol (CBD), one of the major cannabinoids derived from the cannabis plant, is available over the counter. CBD is often used by patients for the management of insomnia, yet research supporting CBDs effectiveness as a treatment for insomnia is inadequate. 

Objective: The objective of this review was to critically evaluate the literature regarding the therapeutic benefits of CBD in the management of insomnia. 

Methods: A comprehensive search of the following databases from inception to December 29, 2021, was conducted: Ovid MEDLINE® and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily, Ovid Embase, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, and Scopus. The search included randomized controlled trials, nonrandomized experimental studies, cross-sectional studies, cohort studies, case series, and case reports. Risk of bias was assessed with the Agency for Healthcare Research and Quality design-specific recommended criteria. 

Results: Thirty-four studies were eligible for inclusion. All studies reported improvement in the insomnia symptoms of at least a portion of their participants. Of the 34 studies, 19 studies used CBD predominant therapy and 21 studies used nearly equal ratios of CBD to Δ9-tetrahydrocannabinol (THC). Of the studies that performed hypothesis testing, 4 of 7 studies with a CBD predominant arm and 12 of 16 studies with a nearly equal ratio of CBD to THC arm reported significant improvement in insomnia outcomes. However, only 2 of the 34 studies focused on patients with insomnia, of which 1 study was a case report. Additionally, several studies used nonvalidated subjective measures, and most studies failed to include objective measures for symptom assessment. 

Conclusions: The results of our systematic review suggest that CBD alone or with equal quantities of THC may be beneficial in alleviating the symptoms of insomnia. Nevertheless, future research assessing CBDs effectiveness in population of patients specifically with insomnia utilizing validated subjective and objective measures is necessary before definitive inferences can be made.”

https://pubmed.ncbi.nlm.nih.gov/36149724/

https://www.liebertpub.com/doi/10.1089/can.2022.0122