Author Archives: David Worrell

An investigation of cannabis use for insomnia in depression and anxiety in a naturalistic sample

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“Background: Little is known about cannabis use for insomnia in individuals with depression, anxiety, and comorbid depression and anxiety. To develop a better understanding of distinct profiles of cannabis use for insomnia management, a retrospective cohort study was conducted on a large naturalistic sample.

Methods: Data were collected using the medicinal cannabis tracking app, Strainprint®, which allows users to monitor and track cannabis use for therapeutic purposes. The current study examined users managing insomnia symptoms in depression (n = 100), anxiety (n = 463), and comorbid depression and anxiety (n = 114), for a total of 8476 recorded sessions. Inferential analyses used linear mixed effects modeling to examine self-perceived improvement across demographic variables and cannabis product variables.

Results: Overall, cannabis was perceived to be efficacious across all groups, regardless of age and gender. Dried flower and oral oil were reported as the most used and most efficacious product forms. In the depression group, all strains were perceived to be efficacious and comparisons between strains revealed indica-dominant (Mdiff = 1.81, 95% CI 1.26-2.36, Padj < .001), indica hybrid (Mdiff = 1.34, 95% CI 0.46-2.22, Padj = .045), and sativa-dominant (Mdiff = 1.83, 95% CI 0.68-2.99, Padj = .028) strains were significantly more efficacious than CBD-dominant strains. In anxiety and comorbid conditions, all strain categories were perceived to be efficacious with no significant differences between strains.

Conclusions: In terms of perceptions, individuals with depression, anxiety, and both conditions who use cannabis for insomnia report significant improvements in symptom severity after cannabis use. The current study highlights the need for placebo-controlled trials investigating symptom improvement and the safety of cannabinoids for sleep in individuals with mood and anxiety disorders.”

https://pubmed.ncbi.nlm.nih.gov/35484520/

Medical cannabis oil for benign essential blepharospasm: a prospective, randomized controlled pilot study

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“Objective: To examine the efficacy and safety of medical cannabis in benign essential blepharospasm (BEB).

Methods: This is a prospective, double-blind, placebo-controlled study. All consecutive adult BEB patients who had been treated with BTX-A injections without success between 3/2019 and 2/2020 were recruited. The study patients were randomly allocated into a treatment and a control (placebo) group in a 1:1 ratio. The treatment group used cannabis drops and the control group used cannabis oil drops during the first 6 weeks of the study, and both groups were treated with the medical cannabis drops during the second 6 weeks. The cannabis dose was gradually increased for each patient depending upon effect and tolerability.

Results: Three patients were included in each group (treatment and control groups). The mean duration of spasm attack during the first 6 weeks was 4.29 min in the treatment group and 73.9 min in the placebo group (P < 0.01). During the last 6 weeks, the treatment group used an average of 6.27 drops and the placebo group used an average of 5.36 drops (P = 0.478). There were 61 spasm events in the treatment group and 94 spasm events in the placebo group (P = 0.05). The mean duration of spasm attack was 1.77 and 8.96 min, respectively (P < 0.01). The side effects were mild, and they included general fatigue, dry mouth, and insomnia.

Conclusions: Medical cannabis can be an effective and safe treatment for BEB as a second line after BTX-A injections when used for 3 months. No significant ocular or systemic side effects was associated with the treatment.”

https://pubmed.ncbi.nlm.nih.gov/35067772/

The Effects of Consuming Cannabis Flower for Treatment of Fatigue

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“Objectives: We measure for the first time how commercially available Cannabis flower products affect feelings of fatigue. Results: On average, 91.94% of people experienced decreased fatigue following consumption with an average symptom intensity reduction of 3.48 points on a 0–10 visual analog scale (SD = 2.70, d = 1.60, p < 0.001). While labeled plant phenotypes (“C. indica,” “C. sativa,” or “hybrid”) did not differ in symptom relief, people that used joints to combust the flower reported greater symptom relief than pipe or vaporizer users. Across cannabinoid levels, tetrahydrocannabinol, and cannabidiol levels were generally not associated with changes in symptom intensity levels. Cannabis use was associated with several negative side effects that correspond to increased feelings of fatigue (e.g., feeling unmotivated, couch-locked) among a minority of users (<24% of users), with slightly more users (up to 37%) experiencing a positive side effect that corresponds to increased energy (e.g., feeling active, energetic, frisky, or productive). Conclusions: The findings suggest that the majority of patients experience decreased fatigue from consumption of Cannabis flower consumed in vivo, although the magnitude of the effect and extent of side effects experienced likely vary with individuals’ metabolic states and the synergistic chemotypic properties of the plant.”

https://www.karger.com/Article/FullText/524057

Vasoprotective Endothelial Effects of Chronic Cannabidiol Treatment and Its Influence on the Endocannabinoid System in Rats with Primary and Secondary Hypertension

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“Our study aimed to examine the endothelium (vascular)-protecting effects of chronic cannabidiol (CBD) administration (10 mg/kg once daily for 2 weeks) in aortas and small mesenteric (G3) arteries isolated from deoxycorticosterone-induced hypertensive (DOCA-salt) rats and spontaneously hypertensive rats (SHR). CBD reduced hypertrophy and improved the endothelium-dependent vasodilation in response to acetylcholine in the aortas and G3 of DOCA-salt rats and SHR. The enhancement of vasorelaxation was prevented by the inhibition of nitric oxide (NO) with L-NAME and/or the inhibition of cyclooxygenase (COX) with indomethacin in the aortas and G3 of DOCA-salt and SHR, respectively. The mechanism of the CBD-mediated improvement of endothelial function in hypertensive vessels depends on the vessel diameter and may be associated with its NO-, the intermediate-conductance calcium-activated potassium channel- or NO-, COX-, the intermediate and the small-conductance calcium-activated potassium channels-dependent effect in aortas and G3, respectively. CBD increased the vascular expression of the cannabinoid CB1 and CB2 receptors and aortic levels of endocannabinoids with vasorelaxant properties e.g., anandamide, 2-arachidonoylglycerol and palmitoyl ethanolamide in aortas of DOCA-salt and/or SHR. In conclusion, CBD treatment has vasoprotective effects in hypertensive rats, in a vessel-size- and hypertension-model-independent manner, at least partly via inducing local vascular changes in the endocannabinoid system.”

https://pubmed.ncbi.nlm.nih.gov/34832902/

Cannabidiol-mediated RISK PI3K/AKT and MAPK/ERK pathways decreasing reperfusion myocardial damage

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“Myocardial ischemia continues to be the first cause of morbimortality in the world; the definitive treatment is reperfusion; however, this action causes additional damage to ischemic myocardial tissue; this forces to seek therapies of cardioprotection to reduce this additional damage. There are many cardioprotective agents; within these, cannabinoids have shown to have beneficial effects, mainly cannabidiol (CBD). CBD is a non psychoactive cannabinoid. To evaluate the effect in experimental models of CBD in myocardial ischemia reperfusion in rats, twelve-week-old male rats have been used. The animals were divides in 3 groups: control(C), ischemia reperfusion (IR) and CBD pretreatment (1/day/5mg/kg /10days). Langendorff organ isolate studies were performed, and the area of infarction was assessed with triphenyl tetrazolium, in addition to molecular analysis of AT1 and AT2 receptors and Akt and Erk proteins and their phosphorylated forms related to RISK pathways. It was observed that there is an improvement with the use of CBD increasing inotropism and cardiac lusitropism, improving considerably the cardiovascular functionality. These could be related to the reduction of the area of infarction and activation of the AT2 receptor and the RISK pathway with absence of activation of the AT2 receptor (these could relate the reduction of the infarct area and the restoration of cardiovascular function with the activation of the AT2 receptor and the RISK pathway with the absence of activation of the AT2 receptor). The use of cannabinoids was shown to have beneficial effects when used as a treatment for myocardial reperfusion damage.”

https://pubmed.ncbi.nlm.nih.gov/34176244/

Δ 9-Tetrahydrocannabinol (Δ 9-THC) Improves Ischemia/Reperfusion Heart Dysfunction and Might Serve as a Cardioprotective Agent in the Future Treatment

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“Background: Ischemia/reperfusion (I/R) is a pivotal mechanism of organ injury during clinical stetting for example for cardiopulmonary bypasses. The generation of reactive oxygen species (ROS) during I/R induces oxidative stress that promotes endothelial dysfunction, DNA dissociation and local inflammation. In turn, those processes induce cytokine release, resulting in damage to cellular structures and cell death. One of the major psychoactive compounds of Cannabis is delta-9-tetrahydrocannabinol (Δ9-THC), which is known as an anti-inflammatory mediator. Our research aimed to test if Δ9-THC may be protective in the treatment of cardiovascular system dysfunction arising from I/R heart injury.

Methods: Two experimental models were used: isolated rat hearts perfused with the Langendorff method and human cardiac myocytes (HCM) culture. Rat hearts and HCM underwent ex vivo/chemical in vitro I/R protocol with/without Δ9-THC treatment. The following parameters were measured: cell metabolic activity, morphology changes, cell damage as lactate dehydrogenase (LDH) activity, ceramide kinase (CERK) activity, ROS level, total antioxidant capacity (TAC) and heart hemodynamic parameters.

Results: Δ9-THC protected the heart, as evidenced by the improved recovery of cardiac function (p < 0.05, N = 3-6). Cells subjected to I/R showed lower cytoplasmic LDH activity, and 10 μM Δ9-THC treatment reduced cell injury and increased LDH content (p = 0.019, N = 6-9). Morphology changes of HCM-spherical shape, vacuolisation of cytoplasm and swollen mitochondria-were inhibited due to Δ9-THC treatment. I/R condition affected cell viability, but 10 μM Δ9-THC decreased the number of dead cells (p = 0.005, N = 6-9). The total level of CERK was lower in the I/R group, reflecting oxidative/nitrosative stress changes. The administration of Δ9-THC effectively increased the production of CERK to the level of aerobic control (p = 0.028, N = 6-9). ROS level was significantly decreased in I/R cells (p = 0.007, N = 6-8), confirming oxidative stress, while administration of 10 μM Δ9-THC enhanced TAC in cardiomyocytes subjected to I/R (p = 0.010, N = 6-8).

Conclusions: Δ9-THC promotes the viability of cardiomyocytes, improves their metabolic activity, decreases cell damage and restores heart mechanical function, serving as a cardioprotective. We proposed the use of Δ9-THC as a cardioprotective drug to be, administered before onset of I/R protocol.”

https://pubmed.ncbi.nlm.nih.gov/35468673/

Marijuana and Myocardial Infarction in the UK Biobank Cohort

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“Background: Atrial fibrillation, ventricular tachycardia, acute coronary syndromes, and cardiac arrest have been attributed to marijuana. But the National Academy of Science’s 2017 Report, The Health Effects of Cannabis and Cannabinoids, found limited evidence that acute marijuana smoking is positively associated with an increased risk of acute myocardial infarction, and uncovered no evidence to support or refute associations between any chronic effects of marijuana use and increased risk of myocardial infarct (MI).

Aims: We sought to determine the association of marijuana smoking with MI in the UK Biobank cohort. Because red wine is a mood-altering substance, we compared the effect of marijuana with red wine on MI incidence.

Methods: Our analysis included all subjects with MI. The diagnosis was ascertained using the 10th Revision of the International Classification of Diseases (ICD10 I21). Marijuana was recorded in UKB Category 143, medical conditions, marijuana use. Cigarette smoking information was from UKB Category 100058, smoking. To compare marijuana smoking with the effect of wine drinking we used data from UKB Category 10051, alcohol.

Results: With marijuana use, MI incidence decreased (p < 0.001, two tail Fisher exact test). Red wine was associated with lower MI incidence, although the incidence begins to rise at 11 or more glasses per week (p < 0.001, two tail Fisher exact test). Multivariate analysis was done with logistic regression, MI dependent variable, cigarette pack-years, diabetes type 2, sex, BMI, hypertension, marijuana use, age, red wine consumption, independent variables. Odds ratio (O.R.) 0.844 associated with marijuana use indicates that MI was less likely in marijuana users and was comparable to the effect of red wine (O.R. 0.847).

Conclusion: Marijuana, which has not been shown to have the favorable physiologic effects of red wine on the heart, does reduce MI risk to an extent comparable to red wine. Perhaps both affect the heart by reducing stress.”

https://pubmed.ncbi.nlm.nih.gov/35165641/

Long-term observational studies with cannabis-based medicines for chronic non-cancer pain: A systematic review and meta-analysis of effectiveness and safety

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“Background and objective: This systematic review evaluated the effectiveness, tolerability and safety of cannabis-based medicines (CbMs) for chronic non-cancer pain (CNCP) in long-term observational studies.

Databases and data treatment: CENTRAL, EMBASE and MEDLINE were searched to December 2021. We included prospective observational studies with a study duration ≥ 26 weeks. Pooled estimates of event rates of categorical data and standardized mean differences (SMD) of continuous variables were calculated using a random effects model.

Results: Six studies were included with 2686 participants, with study duration ranging between 26 and 52 weeks. Pain conditions included were nociceptive, nociplastic, neuropathic and mixed pain. The certainty of evidence for every outcome was very low. The weighted mean difference of mean pain reduction was 1.75 (95% Confidence interval [CI] 0.72 to 2.78) on a 0-10 scale. 20.8 % (95% CI 10.2 % to 34.0 %) of patients reported pain relief of 50% or greater. The effect size for sleep problems was moderate and for depression and anxiety was low. Study completions was reported for 53.3% (95% CI 26.8% to 79.9%) of patients, with dropouts of 6.8 % (95% CI 4.3% to 9.7%) due to adverse events. Serious adverse events occurred in 3.0% (95 CI 0.02 % to 12.8%) and 0.3 % (95% CI 0.1% to 0.6%) of patients died.

Conclusions: Information included in observational studies should be regarded with caution.Within the context of observational studies, CbMs had positive effects on multiple symptoms for some CNCP patients and were generally well tolerated and safe.”

https://pubmed.ncbi.nlm.nih.gov/35467781/

Direct Regulation of Hyperpolarization-Activated Cyclic-Nucleotide Gated (HCN1) Channels by Cannabinoids

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“Cannabinoids are a broad class of molecules that act primarily on neurons, affecting pain sensation, appetite, mood, learning, and memory. In addition to interacting with specific cannabinoid receptors (CBRs), cannabinoids can directly modulate the function of various ion channels. Here, we examine whether cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC), the most prevalent phytocannabinoids in Cannabis sativa, can regulate the function of hyperpolarization-activated cyclic-nucleotide-gated (HCN1) channels independently of CBRs. HCN1 channels were expressed in Xenopus oocytes since they do not express CBRs, and the effects of cannabinoid treatment on HCN1 currents were examined by a two-electrode voltage clamp. We observe opposing effects of CBD and THC on HCN1 current, with CBD acting to stimulate HCN1 function, while THC inhibited current. These effects persist in HCN1 channels lacking the cyclic-nucleotide binding domain (HCN1ΔCNBD). However, changes to membrane fluidity, examined by treating cells with TX-100, inhibited HCN1 current had more pronounced effects on the voltage-dependence and kinetics of activation than THC, suggesting this is not the primary mechanism of HCN1 regulation by cannabinoids. Our findings may contribute to the overall understanding of how cannabinoids may act as promising therapeutic molecules for the treatment of several neurological disorders in which HCN function is disturbed.”

https://pubmed.ncbi.nlm.nih.gov/35465092/

Cannabis sativa L. Bioactive Compounds and Their Protective Role in Oxidative Stress and Inflammation

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“Cannabis (Cannabis sativa L.) plants from the family Cannabidaceae have been used since ancient times, to produce fibers, oil, and for medicinal purposes. Psychoactive delta-9-tetrahydrocannabinol (THC) and nonpsychoactive cannabidiol (CBD) are the main pharmacologically active compounds of Cannabis sativa. These compounds have, for a long time, been under extensive investigation, and their potent antioxidant and inflammatory properties have been reported, although the detailed mechanisms of their actions have not been fully clarified. CB1 receptors are suggested to be responsible for the analgesic effect of THC, while CB2 receptors may account for its immunomodulatory properties. Unlike THC, CBD has a very low affinity for both CB1 and CB2 receptors, and behaves as their negative allosteric modulator. CBD activity, as a CB2 receptor inverse agonist, could be important for CBD anti-inflammatory properties. In this review, we discuss the chemical properties and bioavailability of THC and CBD, their main mechanisms of action, and their role in oxidative stress and inflammation.”

https://pubmed.ncbi.nlm.nih.gov/35453344/