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

Cannabidiol prevents methamphetamine-induced neurotoxicity by modulating dopamine receptor D1-mediated calcium-dependent phosphorylation of methyl-CpG-binding protein 2

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“In the past decade, methamphetamine (METH) abuse has sharply increased in the United States, East Asia, and Southeast Asia. METH abuse not only leads to serious drug dependence, but also produces irreversible neurotoxicity. Currently, there are no approved pharmacotherapies for the treatment of METH use disorders. Cannabidiol (CBD), a major non-psychoactive (and non-addictive) cannabinoid from the cannabis plant, shows neuroprotective, antioxidative, and anti-inflammatory properties under METH exposure. At present, however, the mechanisms underlying these properties remain unclear, which continues to hinder research on its therapeutic potential. In the current study, computational simulations showed that CBD and METH may directly bind to the dopamine receptor D1 (DRD1) via two overlapping binding sites. Moreover, CBD may compete with METH for the PHE-313 binding site. We also found that METH robustly induced apoptosis with activation of the caspase-8/caspase-3 cascade in-vitro and in-vivo, while CBD pretreatment prevented these changes. Furthermore, METH increased the expression of DRD1, phosphorylation of Methyl-CpG-binding protein 2 (MeCP2) at serine 421 (Ser421), and level of intracellular Ca2+ in-vitro and in-vivo, but these effects were blocked by CBD pretreatment. The DRD1 antagonist SCH23390 significantly prevented METH-induced apoptosis, MeCP2 phosphorylation, and Ca2+ overload in-vitro. In contrast, the DRD1 agonist SKF81297 markedly increased apoptosis, MeCP2 phosphorylation, and Ca2+ overload, which were blocked by CBD pretreatment in-vitro. These results indicate that CBD prevents METH-induced neurotoxicity by modulating DRD1-mediated phosphorylation of MeCP2 and Ca2+ signaling. This study suggests that CBD pretreatment may resist the effects of METH on DRD1 by competitive binding.”

https://pubmed.ncbi.nlm.nih.gov/36147353/

“In conclusion, our results suggest that METH induces neurotoxicity via DRD1-mediated calcium-dependent phosphorylation of MeCP2 at Ser421. Moreover, CBD significantly prevents METH-induced neurotoxicity via modulation of DRD1.”

https://www.frontiersin.org/articles/10.3389/fphar.2022.972828/full

Parent and Caregiver Perspectives towards Cannabidiol as a Treatment for Fragile X Syndrome

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“Cannabidiol (CBD) is a non-intoxicating chemical in cannabis plants that is being investigated as a candidate for treatment in Fragile X Syndrome (FXS), a leading known cause of inherited intellectual developmental disability. Studies have shown that CBD can reduce symptoms such as anxiety, social avoidance, hyperactivity, aggression, and sleep problems. This is a qualitative study that utilized a voluntary-anonymous survey that consisted of questions regarding demographics, medical information, the form, type, brand, dose, and frequency of CBD use, the rationale for use, the perception of effects, side effects, and costs. The full survey contained a total of 34 questions, including multiple-choice, Likert-scale, and optional free-response questions. This research revealed that there are a wide range of types, brands, and doses of CBD being administered to individuals with FXS by their parents and caregivers. There were many reasons why CBD was chosen, the most common ones being that respondents had heard positive things about CBD from members of the community, the perception that CBD had fewer side effects than other medications, and because respondents felt that CBD was a more natural substance. Most of the parents and caregivers who responded agreed that CBD improved some of the symptoms of FXS and made a positive difference overall. CBD has the therapeutic potential to help relieve some FXS symptoms. Future research is necessary to understand the benefits of CBD in FXS.”

https://pubmed.ncbi.nlm.nih.gov/36140762/

https://www.mdpi.com/2073-4425/13/9/1594

Cannabis-based magistral formulation is highly effective as an adjuvant treatment in drug-resistant focal epilepsy in adult patients: an open-label prospective cohort study

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“Introduction: The safety and efficacy of a formulation high in cannabidiol (CBD) and low in ∆9-tetrahydrocannabinol (THC) to treat drug-resistant epilepsy have been examined previously in children, but not in adult population. The aim of this study was to evaluate whether CBD-rich oil, as an add-on treatment to conventional antiepileptic drugs, was effective, safe, and well-tolerated in adults with drug-resistant focal epilepsy (DRFE).

Methods: An open-label, prospective cohort, single-center in adult patients with DRFE, were receiving stable doses of antiepileptic drugs (AEDs). A cannabis based-magistral formulation (CBMF) (100 mg/ml CBD and THC <1.9 mg/ml) was administrated 0.1 ml sublingually every 12 hours, up-titrated weekly. The primary outcome was to establish a reduction in seizures frequency >50% at 12 weeks. Adverse-drug reactions monitoring was done. p-value <0.05 was statistically significant.

Results: Between August 2020 and July 2022, 44 (38.6%) patients completed >3 months of follow-up. The median daily dose of CBD was 200 mg, that of THC was 4 mg, and that of CBD per kilogram of weight was 3.7 mg. The median number of seizures per month before CBD treatment was 11, and after CBD treatment was 2.5 (p<0.001). A reduction in seizures >50% at 12 week was achieved in 79.5% of the patients. The median percentage change in seizure frequency per month was 84.1% at 12 weeks. Five patients reported any adverse-drug reactions.

Conclusion: The CBMF is a highly effective and safety therapy to treat adult patients with DRFE. The reduction in seizures frequency is maintained over time.”

https://pubmed.ncbi.nlm.nih.gov/36129615/

https://link.springer.com/article/10.1007/s10072-022-06393-1

Investigation of cannabidiol’s potential targets in limbic seizures. In-silico approach

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“Even though the vast armamentarium of FDA-approved antiepileptic drugs is currently available, over one-third of patients do not respond to medication, which arises a need for alternative medicine. In clinical and preclinical studies, various investigations have shown the advantage of specific plant-based cannabidiol (CBD) products in treating certain groups of people with limbic epilepsy who have failed to respond to conventional therapies. This work aims to investigate possible mechanisms by which CBD possesses its anticonvulsant properties. Molecular targets for CBD’s treatment of limbic epilepsy, including hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1), gamma-aminobutyric acid aminotransferase (GABA-AT), and gamma-aminobutyric acid type A receptor (GABAA), were used to evaluate its binding affinity. Interactions with the CB1 receptor were initially modeled as a benchmark, which further proved the efficiency of proposed here approach. Considering the successful benchmark, we further used the same concept for in silico investigation, targeting proteins of interest. As a result of molecular docking, molecular mechanics, and molecular dynamics simulations models of CBD-receptor complexes were proposed and evaluated. While CBD possessed decently high affinity and stability within the binding pockets of GABA-AT and some binding sites of GABAA, the most effective binding was observed in the CBD complex with HCN1 receptor. 100 ns molecular dynamics simulation revealed that CBD binds the open pore of HCN1 receptor, forming a similar pattern of interactions as potent Lamotrigine. Therefore, we can propose that HCN1 can serve as a most potent target for cannabinoid antiepileptic treatment. Communicated by Ramaswamy H. Sarma.”

https://pubmed.ncbi.nlm.nih.gov/36129109/

https://www.tandfonline.com/doi/abs/10.1080/07391102.2022.2124454?journalCode=tbsd20

Effects of rich cannabidiol oil on behavioral disturbances in patients with dementia: A placebo controlled randomized clinical trial

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“Background: Almost 90% of patients with dementia suffer from some type of neurobehavioral symptom, and there are no approved medications to address these symptoms.

Objective: To evaluate the safety and efficacy of the medical cannabis oil “Avidekel” for the reduction of behavioral disturbances among patients with dementia.

Materials and methods: In this randomized, double-blind, single-cite, placebo-controlled trial conducted in Israel (ClinicalTrials.gov: NCT03328676), patients aged at least 60, with a diagnosis of major neurocognitive disorder and associated behavioral disturbances were randomized 2:1 to receive either “Avidekel,” a broad-spectrum cannabis oil (30% cannabidiol and 1% tetrahydrocannabinol: 295 mg and 12.5 mg per ml, respectively; n = 40) or a placebo oil (n = 20) three times a day for 16 weeks. The primary outcome was a decrease, as compared to baseline, of four or more points on the Cohen-Mansfield Agitation Inventory score by week 16.

Results: From 60 randomized patients [mean age, 79.4 years; 36 women (60.0%)], 52 (86.7%) completed the trial (all eight patients who discontinued treatment were from the investigational group). There was a statistically significant difference in the proportion of subjects who had a Cohen-Mansfield Agitation Inventory score reduction of ≥ 4 points at week 16: 24/40 (60.0%) and 6/20 (30.0%) for investigational and control groups, respectively (χ2 = 4.80, P = 0.03). There was a statistically significant difference in the proportion of subjects who had a Cohen-Mansfield Agitation Inventory score reduction of ≥ 8 points at week 16: 20/40 (50%) and 3/20 (15%), respectively (χ2 = 6.42, P = 0.011). The ANOVA repeated measures analysis demonstrated significantly more improvement in the investigational group compared to the control group at weeks 14 and 16 (F = 3.18, P = 0.02). Treatment was mostly safe, with no significant differences in the occurrence of adverse events between the two groups.

Conclusion: In this randomized controlled trial, ‘Avidekel’ oil significantly reduced agitation over placebo in patients suffering from behavioral disturbances related to dementia, with non-serious side-effects. Further research is required with a larger sample size.”

https://pubmed.ncbi.nlm.nih.gov/36148467/

“Our findings suggest that rich-CBD cannabis oil may alleviate agitation in older patients with dementia.”

https://www.frontiersin.org/articles/10.3389/fmed.2022.951889/full

Preoperative cannabis use does not increase opioid utilization following primary total hip arthroplasty in a propensity matched analysis

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“Purpose: The recreational and medical use of cannabis is being legalized worldwide. Its use has been linked to an increased risk of developing opioid use disorders. As opioids continue to be prescribed after total hip arthroplasty (THA), the influence that preoperative cannabis use may have on postoperative opioid consumption remains unknown. The purpose of this study was to assess the relationship between preoperative cannabis use and opioid utilization following primary THA.

Methods: We identified all patients over the age of 18 who underwent unilateral, primary THA for a diagnosis of osteoarthritis at a single institution from February 2019 to April 2021. Our cohort was grouped into current cannabis users (within 6 months of surgery) and those who reported never using cannabis. One hundred and fifty-six current users were propensity score matched 1:6 with 936 never users based on age, sex, BMI, history of chronic pain, smoking status, history of anxiety/depression, ASA classification and type of anesthesia. Outcomes included inpatient and postdischarge opioid use in morphine milligram equivalents.

Results: Total inpatient opioid utilization, opioids refilled, and total opioids used within 90 postoperative days were similar between the groups.

Conclusion: In propensity score matched analyses, preoperative cannabis use was not independently associated with an increase in inpatient or outpatient, 90-days opioid consumption following elective THA.”

https://pubmed.ncbi.nlm.nih.gov/36129515/

https://link.springer.com/article/10.1007/s00402-022-04619-7

Does cannabis use predict aggressive or violent behavior in psychiatric populations? A systematic review

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“Background: Despite an increase in information evaluating the therapeutic and adverse effects of cannabinoids, many potentially important clinical correlates, including violence or aggression, have not been adequately investigated.Objectives: In this systematic review, we examine the published evidence for the relationship between cannabis and aggression or violence in individuals with psychiatric disorders.Methods: Following PRISMA guidelines, articles in English were searched on PubMed, Google Scholar, MEDLINE, and PsycINFO from database inception to January 2022. Data for aggression and violence in people with psychiatric diagnoses were identified during the searches.Results: Of 391 papers identified within the initial search, 15 studies met inclusion criteria. Cross-sectional associations between cannabis use and aggression or violence in samples with post-traumatic stress disorder (PTSD) were found. Moreover, a longitudinal association between cannabis use and violence and aggression was observed in psychotic-spectrum disorders. However, the presence of uncontrolled confounding factors in the majority of included studies precludes any causal conclusions.Conclusion: Although cannabis use is associated with aggression or violence in individuals with PTSD or psychotic-spectrum disorders, causal conclusions cannot be drawn due to methodological limitations observed in the current literature. Well-controlled, longitudinal studies are needed to ascertain whether cannabis plays a causal role on subsequent violence or aggression in mental health disorders.”

https://pubmed.ncbi.nlm.nih.gov/36137273/

https://www.tandfonline.com/doi/abs/10.1080/00952990.2022.2118060?journalCode=iada20

Cannabidiol and Delta-9-Tetrahydrocannabinol Interactions in Male and Female Rats with Persistent Inflammatory Pain

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The Journal of Pain

“Cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC), two of the primary constituents of cannabis, are used by some individuals to self-treat chronic pain. It is unclear whether the pain-relieving effects of CBD alone and in combination with THC are consistent across genders and among types of pain.

The present study compared the effects of CBD and THC given alone and in combination in male and female rats with Complete Freund’s adjuvant-induced inflammatory pain.

After induction of hindpaw inflammation, vehicle, CBD (0.05-2.5 mg/kg), THC (0.05-2.0 mg/kg), or a CBD:THC combination (3:1, 1:1, or 1:3 dose ratio) was administered i.p. twice daily for three days. Then on day four, mechanical allodynia, thermal hyperalgesia, weight-bearing, and locomotor activity were assessed 0.5-4 h after administration of the same dose combination. Hindpaw edema and open field (anxiety-like) behaviors were measured thereafter.

THC alone was anti-allodynic and anti-hyperalgesic, and decreased paw thickness, locomotion, and open field behaviors. CBD alone was anti-allodynic and anti-hyperalgesic. When combined with THC, CBD tended to decrease THC effects on pain-related behaviors and exacerbate THC-induced anxiety-like behaviors, particularly in females.

These results suggest that at the doses tested, CBD-THC combinations may be less beneficial than THC alone for the treatment of chronic inflammatory pain.

PERSPECTIVE: The present study compared CBD and THC effects alone and in combination in male and female rats with persistent inflammatory pain. This study could help clinicians who prescribe cannabis-based medicines for inflammatory pain conditions determine which cannabis constituents may be most beneficial.”

https://pubmed.ncbi.nlm.nih.gov/36122809/

“THC and CBD each reduced chronic inflammatory pain (allodynia and hyperalgesia) in rats.”

https://www.jpain.org/article/S1526-5900(22)00392-3/fulltext

Therapeutic properties of multi-cannabinoid treatment strategies for Alzheimer’s disease

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“Alzheimer’s disease (AD) is a debilitating neurodegenerative disease characterized by declining cognition and behavioral impairment, and hallmarked by extracellular amyloid-β plaques, intracellular neurofibrillary tangles (NFT), oxidative stress, neuroinflammation, and neurodegeneration. There is currently no cure for AD and approved treatments do not halt or slow disease progression, highlighting the need for novel therapeutic strategies.

Importantly, the endocannabinoid system (ECS) is affected in AD. Phytocannabinoids, including cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC), interact with the ECS, have anti-inflammatory, antioxidant, and neuroprotective properties, can ameliorate amyloid-β and NFT-related pathologies, and promote neurogenesis. Thus, in recent years, purified CBD and THC have been evaluated for their therapeutic potential.

CBD reversed and prevented the development of cognitive deficits in AD rodent models, and low-dose THC improved cognition in aging mice. Importantly, CBD, THC, and other phytochemicals present in Cannabis sativa interact with each other in a synergistic fashion (the “entourage effect”) and have greater therapeutic potential when administered together, rather than individually. Thus, treatment of AD using a multi-cannabinoid strategy (such as whole plant cannabis extracts or particular CBD:THC combinations) may be more efficacious compared to cannabinoid isolate treatment strategies.

Here, we review the current evidence for the validity of using multi-cannabinoid formulations for AD therapy. We discuss that such treatment strategies appear valid for AD therapy but further investigations, particularly clinical studies, are required to determine optimal dose and ratio of cannabinoids for superior effectiveness and limiting potential side effects. Furthermore, it is pertinent that future in vivo and clinical investigations consider sex effects.”

https://pubmed.ncbi.nlm.nih.gov/36117622/

“This mini review highlights that multi-cannabinoid combination treatment strategies are valid candidates for novel AD therapies. However, further investigations, and in particular, clinical studies, are required to determine optimal dose and ratio of cannabinoids for treatment of behavioral, cognitive, and pathological symptoms of AD thereby also considering other cannabinoids in addition to the current focus on THC and CBD (most cannabis extract studies did not profile cannabinoid content beyond those two phytocannabinoids). Importantly, all relevant studies reviewed were carried out in one sex/gender only. Given that sex-specificity is evident in AD transgenic mouse models (van Eersel et al., 2015; Jiao et al., 2016) and gender differences are seen in dementia (Oveisgharan et al., 2018) as well as in the ECS and the response to cannabis (Craft et al., 2013), it is pertinent that these future investigations consider both sexes.”

https://www.frontiersin.org/articles/10.3389/fnins.2022.962922/full