Author Archives: David

Emerging trends in cannabis administration for women with chronic pain

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“Cannabis use among women who experience chronic pain is on the rise in the United States. However, little is known about women’s motives and preferences for cannabis administration. The purpose of this study was to characterize cannabis use among women with chronic pain.

This study examined self-reported forms of cannabis administration and preferred source of cannabis, frequency and quantity of use, and self-reported side effects, and type, level, and intensity of chronic pain among adult women in the United States. This study also compared women who use cannabis for chronic pain and those who do not across the level of chronic pain, length of chronic pain, and the number of types of chronic pain experienced.

Participants showed a significant preference (60%) for using recreational cannabis to treat chronic pain but reported that medical cannabis was more effective. For participants who preferred medical cannabis 24.3% reported daily use, as compared to only 7.8% of recreational cannabis users. Smoking was the most common form of administration (62.1%), followed by edibles (25.3%), vaporizing in any form (7.4%), tinctures and concentrates (3.2%), and topicals (2.1%). Participants reported using 1-6 different forms of cannabis administration. Those who preferred smoking were significantly likely to use all other forms of administration. However, those who preferred alternatives to smoking were significantly likely to use all forms of administration except for smoking. Medical cannabis users preferred to obtain cannabis from a dispensary, while recreational users preferred to obtain cannabis from unlicensed sources.

Additionally, participants who used cannabis for chronic pain reported a 74% reduction in past 30-day opioid use.

Future research is needed to investigate the health effects associated with single and combined forms of cannabis administration for women with chronic pain. Results can inform educational and intervention programs, treatment development, content regulation of products, policy formation, women’s health research, and public health guidelines.”

https://pubmed.ncbi.nlm.nih.gov/39816373/

https://onlinelibrary.wiley.com/doi/10.1002/mhs2.88

Cannabidiol abrogates cue-induced anxiety associated with normalization of mitochondria-specific transcripts and linoleic acid in the nucleus accumbens shell

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“Anxiety disorders are one of the top contributors to psychiatric burden worldwide. Recent years have seen a dramatic rise in the potential anxiolytic properties ascribed to cannabidiol (CBD), a non-intoxicating constituent of the Cannabis Sativa plant.

This has led to several clinical trials underway to examine the therapeutic potential of CBD for anxiety disorders. Yet, CBD’s anxiolytic effects are mixed with some studies reporting little to no impact on trait anxiety but significant reductions in pathological anxiety with suggestions that CBD’s effect may relate to triggered or cue-induced behavior.

Here, we studied the effects of CBD on cued and non-cued behaviors and related neurobiological underpinnings. To investigate the effect of CBD on cue-induced anxiety, male rats underwent a fear conditioning protocol (odor associated with shock) followed by assessments of avoidance behavior. CBD (10 mg/kg) was administered 1 h prior to anxiety assessments. To understand molecular mechanisms associated with behavior, we investigated the transcriptome and lipid profile of the nucleus accumbens shell (NAcSh), a structure implicated in cue-mediated behaviors and aversion.

Administration of CBD significantly reduced avoidance behavior, but only in animals repeatedly exposed to a shock-paired cue. CBD did not affect behavior in animals exposed to neutral cue or encoding of the cue behavioral response. RNA sequencing revealed substantial impact of the shock-paired cue in control animals, recruiting mechanisms ranging from cytoskeletal dynamics to mitochondria dysfunction. The shock-paired cue also resulted in elevated linoleic acid in vehicle animals which correlated with anxiety-like behavior. CBD either reversed or normalized these cue-induced molecular phenotypes. CBD also recruited lipid networks which correlated with transcripts involved in synaptic plasticity, signaling, and epigenetic mechanisms.

These results suggest that CBD may specifically alleviate salient, conditioned anxiety and normalize related biological mechanisms in the NAcSh which may guide therapeutic interventions for anxiety disorders.”

https://pubmed.ncbi.nlm.nih.gov/39815058/

https://www.nature.com/articles/s41380-024-02881-2

Cannabinoid-based Pharmacology for the Management of Substance Use Disorders

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“In the last two decades, the endocannabinoid system has emerged as a crucial modulator of motivation and emotional processing. Due to its widespread neuroanatomical distribution and characteristic retrograde signaling nature, cannabinoid type I receptors and their endogenous ligands finely orchestrate somatic and axon terminal activity of dopamine neurons.

Owing to these unique features, this signaling system is a promising pharmacological target to ameliorate dopamine-mediated drug-seeking behaviors while circumventing the adverse side effects of, for instance, dopaminergic antagonists.

Despite considerable preclinical efforts, an agreement on the efficacy of endocannabinoid-targeting compounds for treating drug substance use disorders in humans has not been reached. In the following chapter, we will summarize preclinical and clinical evidence addressing the therapeutic potential of cannabinoids and endocannabinoid-targeting compounds in substance use disorders.

To bridge the gap between animal and clinical research, we capitalize on studies evaluating the impact of endocannabinoid-targeting compounds in relevant settings, such as the management of drug relapse.

Finally, we discuss the therapeutic potential of novel cannabinoid compounds that hold promise for treating substance use disorders.”

https://pubmed.ncbi.nlm.nih.gov/39813001/

https://link.springer.com/chapter/10.1007/7854_2024_551

Determination of the Negative Allosteric Binding Site of Cannabidiol at the CB1 Receptor: A Combined Computational and Site-Directed Mutagenesis Study

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“Cannabinoid receptor 1 (CB1R) has been extensively studied as a potential therapeutic target for various conditions, including pain management, obesity, emesis, and metabolic syndrome. Unlike orthosteric agonists such as Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD) has been identified as a negative allosteric modulator (NAM) of CB1R, among its other pharmacological targets. Previous computational and structural studies have proposed various binding sites for CB1R NAMs. An X-ray crystal structure revealed a binding site for the NAM, ORG27569, at an extrahelical location within the inner leaflet of the membrane. In contrast, multiple computational studies have previously proposed several potential allosteric binding sites for CBD within the CB1R structure. Given that a prior structural study suggested CBD might occupy the same site as ORG27569, we conducted a comprehensive investigation of potential CBD binding sites using molecular docking, molecular dynamics (MD) simulations, metadynamics (MTD) simulations, binding free-energy calculations, and in vitro mutagenesis experiments. Molecular docking, MD, and MTD simulations results, along with binding free-energy calculations, suggest that CBD may potentially bind to either the same extrahelical site as ORG27569 or a previously unidentified intracellular site located near TMHs 2, 6, and 7 and helix 8. This intracellular site is consistent with allosteric binding sites observed in other G protein-coupled receptors (GPCRs). To establish the most favorable allosteric site for CBD, we conducted site-directed mutagenesis of key residues at each site. Mutations at S4018.47ΔA and D4038.49ΔA augmented the binding of [3H]-SR141716A, suggesting these residues play critical roles in CBD binding. As a result, the combined computational and mutagenesis results identified a binding site for CBD between TMHs 2, 6, and 7 and helix 8, involving residues Y1532.40, I1562.43, M3376.29, L3416.33, S4018.47, and D4038.49. These findings provide valuable insights into how CBD binds to CB1R, thereby informing the rational design of new, selective, and potent NAMs. Moreover, the elucidation of this previously unexplored allosteric site might explain the polypharmacology of CBD due to structural conservation among Class A GPCRs.”

https://pubmed.ncbi.nlm.nih.gov/39812521/

https://pubs.acs.org/doi/10.1021/acschemneuro.4c00343

An Unexpected Activity of a Minor Cannabinoid: Cannabicyclol (CBL) Is a Potent Positive Allosteric Modulator of Serotonin 5-HT1A Receptor

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“Cannabicyclol ((±)-CBL), a minor phytocannabinoid, is largely unexplored, with its biological activity previously undocumented. We studied its conversion from cannabichromene (CBC) using various acidic catalysts. Montmorillonite (K30) in chloroform at room temperature had the highest yield (60%) with minimal byproducts. Key reaction conditions, such as solvent, temperature, and time, significantly impacted the yield. The structure of (±)-CBL was confirmed via X-ray crystallography. Stability studies showed that (±)-CBL and its MCT oil dilution remain stable at 25-40 °C for three months. Radioligand binding assays revealed high affinity of CBL for the 5-HT1A receptor but weak interaction with CB1 and CB2 receptors. At 10 μM and 1 μM, (±)-CBL inhibited [3H]-8-hydroxy-DPAT binding to 5-HT1A by 75% and 20%, respectively. Functional assays showed that (±)-CBL acts as a weak agonist at high concentrations but a potent positive allosteric modulator of serotonin-induced activation at low concentrations. At 4 μM, (±)-CBL increased serotonin-induced β-arrestin recruitment from 20% to 80%. This unique modulatory profile highlights the potential of (±)-CBL in drug discovery targeting serotonin receptors.”

https://pubmed.ncbi.nlm.nih.gov/39811943/

https://pubs.acs.org/doi/10.1021/acs.jnatprod.4c00977

“Positive allosteric modulators of the 5-HT1A receptor can help relieve anxiety and depression.”

Plant-Derived Compounds in Hemp Seeds (Cannabis sativa L.): Extraction, Identification and Bioactivity-A Review

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“The growing demand for plant-based protein and natural food ingredients has further fueled interest in exploring hemp seeds (Cannabis sativa L.) as a sustainable source of and nutrition.

In addition to the content of proteins and healthy fats (linoleic acid and alpha-linolenic acid), hemp seeds are rich in phytochemical compounds, especially terpenoids, polyphenols, and phytosterols, which contribute to their bioactive properties.

Scientific studies have shown that these compounds possess significant antioxidant, antimicrobial, and anti-inflammatory effects, making hemp seeds a promising ingredient for promoting health. Since THC (tetrahydrocannabinol) and CBD (cannabidiol) are found only in traces, hemp seeds can be used in food applications because the psychoactive effects associated with cannabis are avoided.

Therefore, the present article reviews the scientific literature on traditional and modern extraction methods for obtaining active substances that meet food safety standards, enabling the transformation of conventional foods into functional foods that provide additional health benefits and promote a balanced and sustainable diet.

Also, the identification methods of biologically active compounds extracted from hemp seeds and their bioactivity were evaluated. Mechanical pressing extraction, steam distillation, solvent-based methods (Soxhlet, maceration), and advanced techniques such as microwave-assisted and supercritical fluid extraction were evaluated. Identification methods such as high-performance liquid chromatography (HPLC) and mass spectrometry (MS) allowed for detailed chemical profiling of cannabinoids, terpenes, and phenolic substances.

Optimizing extraction parameters, including solvent type, temperature, and time, is crucial for maximizing yield and purity, offering the potential for developing value-added foods with health benefits.”

https://pubmed.ncbi.nlm.nih.gov/39795183/

https://www.mdpi.com/1420-3049/30/1/124

Cannabinoids: Role in Neurological Diseases and Psychiatric Disorders

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“An impact of legalization and decriminalization of marijuana is the gradual increase in the use of cannabis for recreational purposes, which poses a potential threat to society and healthcare systems worldwide. However, the discovery of receptor subtypes, endogenous endocannabinoids, and enzymes involved in synthesis and degradation, as well as pharmacological characterization of receptors, has led to exploration of the use of cannabis in multiple peripheral and central pathological conditions.

The role of cannabis in the modulation of crucial events involving perturbed physiological functions and disease progression, including apoptosis, inflammation, oxidative stress, perturbed mitochondrial function, and the impaired immune system, indicates medicinal values.

These events are involved in most neurological diseases and prompt the gradual progression of the disease. At present, several synthetic agonists and antagonists, in addition to more than 70 phytocannabinoids, are available with distinct efficacy as a therapeutic alternative in different pathological conditions. The present review aims to describe the use of cannabis in neurological diseases and psychiatric disorders.”

https://pubmed.ncbi.nlm.nih.gov/39796008/

“Cannabis sativa L. (marijuana), an ancient plant with medicinal values, has been used for medicinal, recreational, and spiritual purposes for a long time worldwide.”

“The discovery of the ECS has sparked the interest of many researchers worldwide due to its potential therapeutic contribution to some of the incurable neurodegenerative diseases such as AD, PD, HD, and psychological abnormalities. To date, studies have uncovered the expression, location, structures, and mechanism of cannabinoid receptors.

When the endocannabinoid system’s associations with other biochemical pathways are fully elucidated, many medical and political changes will be seen, such as the legalization of marijuana and new therapeutic approaches to neurodegenerative diseases.

Recent developments regarding crystal structure and cryoEM open the door to understanding the structural complexity and future therapeutic implication of cannabinoids in neurological and psychiatric disorders. Most genes associated with neurological diseases have been defined; however, the molecular details of other changes are largely elusive and are of immense interest to be explored. At this stage, it will be interesting to elucidate the role of CB2R as a neuroprotective strategy in addition to other proteins that are modulated following cannabis administration.

Neuroinflammation, oxidative stress, and disrupted cell organelles, specifically mitochondria, are intimately associated with compelling causative factors for disease progression and are potential therapeutic avenues to explore in neurodegeneration, along with psychological disturbances; therefore, they should be the prime objective for future studies on cannabinoids to develop novel therapeutic chimeric molecules with minimum side effects and maximum benefits.”

https://www.mdpi.com/1422-0067/26/1/152

Effects of a Cannabinoid-Based Phytocomplex (Pain ReliefTM) on Chronic Pain in Osteoarthritic Dogs

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“Twenty-one adult crossbreed dogs with chronic pain due to severe osteoarthrosis were enrolled in the study (placebo vs. treatment groups). The dogs in the experimental group received the dietary supplement (Pain ReliefTM, Giantec, Isernia, Italy) for 30 days to evaluate its effects on metabolism and pain relief. During the trial, the Helsinki Chronic Pain Index significantly decreased (p < 0.01) in the experimental group, indicating reduced pain and improved quality of life. Additionally, the treated group showed improvements in oxidative stress, demonstrated by a reduction in reactive oxygen metabolites, and an increase in biological antioxidant potential. Interleukins 6 levels decreased in the treated group, while interleukins 10 levels increased, thus suggesting an anti-inflammatory effect of the supplement. Importantly, no adverse effects were observed. Results suggest that Pain ReliefTM is effective in ameliorating osteoarthritis in dogs, improving their quality of life.”

https://pubmed.ncbi.nlm.nih.gov/39795044/

“Chronic pain is one of the most disabling conditions in dogs, as it affects various aspects of a dog’s life and should be managed regardless of the severity of symptoms. This research investigates the effects of a cannabidiol-based nutritional supplement in dogs affected by severe osteoarthritis. The treated group showed a reduction in pain due to an improvement of some cytokines expression and oxidative status. This suggests that Pain ReliefTM possesses an anti-inflammatory effect and reduces pain perception in dogs, thereby enhancing their quality of life.”

https://www.mdpi.com/2076-2615/15/1/101

Chronic oral dosing of cannabidiol and cannabidiolic acid full-spectrum hemp oil extracts has no adverse effects in horses: a pharmacokinetic and safety study

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“Objective: To compare the pharmacokinetics of cannabidiol (CBD) and cannabidiolic acid (CBDA) in horses and to evaluate the safety of their chronic administration.

Methods: CBD- and CBDA-rich oil (1 mg/kg) were administered orally twice daily to 7 adult horses over 6 weeks in a randomized, crossover design with a 2-week washout period. A 12-hour pharmacokinetic analysis was conducted on day 1 of each 6-week trial, followed by the measurement of peak and trough concentrations at weeks 1, 2, 4, and 6. The cannabinoids safety was assessed via daily physical examination, periodic bloodwork, and liver biopsy at the beginning and end of the study.

Results: 12-hour pharmacokinetics revealed a higher maximum serum concentration (103 vs 12 ng/mL) and greater area under the curve (259 vs 62 ng·h/mL) for CBDA when compared to CBD. Cannabidiolic acid nadir and peak serum levels over time ranged from 46 to 122 ng/mL, which was higher than CBD (12 to 38 ng/mL). Complete blood count and serum chemistry revealed no clinically relevant changes with either CBD or CBDA. No significant abnormalities were detected on liver ultrasonographic and histopathologic evaluation on day 0 and after both phases of the study.

Conclusions: A dose of either 1 mg/kg of CBD or CBDA administered long term appears safe; however, CBDA serum concentrations suggest superior absorption/retention.

Clinical relevance: Chronic cannabinoid supplementation in horses is safe. Considering the higher absorption of CBDA, its use is recommended to evaluate the therapeutic efficacy of this common hemp derived cannabinoid.”

https://pubmed.ncbi.nlm.nih.gov/39787699/

https://avmajournals.avma.org/view/journals/ajvr/aop/ajvr.24.08.0235/ajvr.24.08.0235.xml

Cannabidiol Alleviates Intestinal Fibrosis in Mice with Ulcerative Colitis by Regulating Transforming Growth Factor Signaling Pathway

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“Objective: The aim of this study is to investigate the protective effect of Cannabidiol (CBD) on DSS-induced colitis in C57BL/6 mice and its related pathways.

Methods: A mouse model of ulcerative colitis (US) was induced by DSS. Enzyme-linked immunosorbent assay (ELISA), quantitative reverse transcription polymerase-chain reaction (qRT-PCR), Western blot (WB) and immunofluorescence (IF) were used to identify the key factors involved in inflammatory response, oxidative stress and intestinal fibrosis. In addition, we transfected si-RNA into CCD-18Co cells.

Results: The research suggests that CBD significantly improves intestinal inflammation by up-regulating the nuclear factor erythroid 2-related factor 2 (Nrf2) expression, inhibiting the classical Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κb) pathway, and inhibiting the release of IL-6 (Interleukin), IL-1β, Tumor Necrosis Factor-α (TNF-α) and other factors. At the same time, CBD plays an antioxidant role by regulating Nrf2/ HO-1 (Heme Oxygenase-1) pathway and activating HO-1 activity. On the other hand, CBD may regulate Transforming growth factor beta (TGF-β)/SMADs signaling pathway by inhibiting the expression of TGF-β1, thereby inhibiting the expression of α-SMA, Collagen1, TIMP1 and other factors, thus playing an anti-fibrotic role. Notably, when Nrf2 is inhibited or lacking, CBD loses the above protective effect against DSS-induced colon injury.

Conclusion: CBD affects the classical NF-κb pathway, Nrf2/ Heme Oxygenase-1 (HO-1) pathway, and Transforming growth factor beta (TGF-β)/SMAD pathway by regulating Nrf2, thereby reducing colonic inflammation and oxidative stress and improving the progression of colonic fibrosis.”

https://pubmed.ncbi.nlm.nih.gov/39802511/

“Taken together, our study demonstrated that CBD affected the classical NF-κb pathway, Nrf2/HO-1 pathway, and TGF-β1/SMAD pathway by regulating Nrf2, thereby reducing intestinal inflammation, oxidative stress and intestinal fibrosis, improving intestinal function and pathological symptoms, and thereby protecting against DSS-induced colon injury. These findings provide new ideas and directions for the treatment of UC.”

https://www.dovepress.com/cannabidiol-alleviates-intestinal-fibrosis-in-mice-with-ulcerative-col-peer-reviewed-fulltext-article-JIR