Biomedicines

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4 pages, 210 KiB

Open AccessEditorial

Special Issue: Therapeutic Potential for Cannabis and Cannabinoids

by Wesley M. Raup-Konsavage

Biomedicines 2023, 11(3), 902; https://doi.org/10.3390/biomedicines11030902 - 14 Mar 2023

Cited by 1 | Viewed by 2686

Abstract

The number of patients reporting the use of cannabis for medical purposes, whether through state-regulated medical marijuana programs or through over-the-counter hemp extracts, continues to grow [...] Full article

(This article belongs to the Special Issue Therapeutic Potential for Cannabis and Cannabinoids)

Research

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10 pages, 236 KiB

Open AccessArticle

A Longitudinal Observational Study of Medical Cannabis Use and Polypharmacy among Patients Presenting to Dispensaries in Pennsylvania

by Emily R. Hajjar, Allison Herens, Erin L. Kelly, Kayla Madden, Jessica M. Lungen and Brooke K. Worster

Biomedicines 2023, 11(1), 158; https://doi.org/10.3390/biomedicines11010158 - 8 Jan 2023

Cited by 3 | Viewed by 3002

Abstract

Background: Cannabis use is increasing among adults to treat a variety of health conditions. Given the potential for interactions and adverse events, it is important to assess the use of medical cannabis along with other concomitant medications when assessing for polypharmacy. Methods: The [...] Read more.

Background: Cannabis use is increasing among adults to treat a variety of health conditions. Given the potential for interactions and adverse events, it is important to assess the use of medical cannabis along with other concomitant medications when assessing for polypharmacy. Methods: The objective of this observational, longitudinal study was to examine medical cannabis (MC) use along with concomitant medications over 12 months in patients with serious medical conditions enrolled in the Pennsylvania (PA) Department of Health’s (DOH) Medical Marijuana Program and to collect and catalog which forms of MC patients are taking along with their concomitant medications. Results: There were 213 participants who completed the baseline surveys in full, and 201, 187, and 175 who completed the 1, 6, and 12-month follow-up surveys. The mean age of the participants was 41.3 years, and 54.5% were female. The mean number of MC products taken at baseline was 3.41 and 3.47 at the 12-month survey. Participants took an average of 3.76 (SD 3.15) medications at baseline and 3.65 (SD 3.4) at 12 months. Most commonly used concomitant medications at baseline included vitamins (42.3%), antidepressants (29.1%), analgesics (22.1%), herbal products (19.7%), and anxiolytics (17.8%). Conclusion: Participants used multiple medical cannabis products to treat a number of medication conditions in conjunction with multiple medications. Full article

(This article belongs to the Special Issue Therapeutic Potential for Cannabis and Cannabinoids)

17 pages, 5602 KiB

Open AccessArticle

Cannabidiol Decreases Intestinal Inflammation in the Ovariectomized Murine Model of Postmenopause

by Karen Mae A. Bacalia, Kevin M. Tveter, Hayley Palmer, Jeffrey Douyere, Savannah Martinez, Ke Sui and Diana E. Roopchand

Biomedicines 2023, 11(1), 74; https://doi.org/10.3390/biomedicines11010074 - 28 Dec 2022

Cited by 4 | Viewed by 3815

Abstract

Cannabidiol (CBD) (25 mg/kg peroral) treatment was shown to improve metabolic outcomes in ovariectomized (OVX) mice deficient in 17β-estradiol (E2). Herein, CBD effects on intestinal and hepatic bile acids (BAs) and inflammation were investigated. Following RNA sequencing of colon tissues from vehicle (VEH)- [...] Read more.

Cannabidiol (CBD) (25 mg/kg peroral) treatment was shown to improve metabolic outcomes in ovariectomized (OVX) mice deficient in 17β-estradiol (E2). Herein, CBD effects on intestinal and hepatic bile acids (BAs) and inflammation were investigated. Following RNA sequencing of colon tissues from vehicle (VEH)- or CBD-treated sham surgery (SS) or OVX mice (n = 4 per group), differentially expressed genes (DEGs) were sorted in ShinyGO. Inflammatory response and bile secretion pathways were further analyzed. Colon content and hepatic BAs were quantified by LC-MS (n = 8–10 samples/group). Gut organoids were treated with CBD (100, 250, 500 µM) with or without TNFα and lipopolysaccharide (LPS) followed by mRNA extraction and qPCR to assess CBD-induced changes to inflammatory markers. The expression of 78 out of 114 inflammatory response pathway genes were reduced in CBD-treated OVX mice relative to vehicle (VEH)-treated OVX mice. In contrast, 63 of 111 inflammatory response pathway genes were increased in CBD-treated sham surgery (SS) mice compared to VEH-treated SS group and 71 of 121 genes were increased due to ovariectomy. CBD did not alter BA profiles in colon content or liver. CBD repressed Tnf and Nos2 expression in intestinal organoids in a dose-dependent manner. In conclusion, CBD suppressed colonic inflammatory gene expression in E2-deficient mice but was pro-inflammatory in E2-sufficient mice suggesting CBD activity in the intestine is E2-dependent. Full article

(This article belongs to the Special Issue Therapeutic Potential for Cannabis and Cannabinoids)

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18 pages, 3321 KiB

Open AccessArticle

Differential Regulation of MMPs, Apoptosis and Cell Proliferation by the Cannabinoid Receptors CB1 and CB2 in Vascular Smooth Muscle Cells and Cardiac Myocytes

by Bettina Greiner, Manuela Sommerfeld, Ulrich Kintscher, Thomas Unger, Kai Kappert and Elena Kaschina

Biomedicines 2022, 10(12), 3271; https://doi.org/10.3390/biomedicines10123271 - 16 Dec 2022

Cited by 4 | Viewed by 2023

Abstract

Cannabinoids (CB) are implicated in cardiovascular diseases via the two main receptor subtypes CB₁R and CB₂R. This study investigated whether cannabinoids regulate the activity of matrix metalloproteases (MMP-2, MMP-9) in vascular smooth muscle cells (VSMCs) and in cells of [...] Read more.

Cannabinoids (CB) are implicated in cardiovascular diseases via the two main receptor subtypes CB₁R and CB₂R. This study investigated whether cannabinoids regulate the activity of matrix metalloproteases (MMP-2, MMP-9) in vascular smooth muscle cells (VSMCs) and in cells of cardiac origin (H9c2 cell line). The influence of CB₁- and CB₂ receptor stimulation or inhibition on cell proliferation, apoptosis and glucose uptake was also evaluated. We used four compounds that activate or block CB receptors: arachidonyl-2-chloroethylamide (ACEA)—CB₁R agonist, rimonabant—CB₁R antagonist, John W. Huffman (JWH133)—CB₂R agonist and CB₂R antagonist—6-Iodopravadoline (AM630). Treatment of cells with the CB₂R agonist JWH133 decreased cytokine activated secretion of proMMP-2, MMP-2 and MMP-9, reduced Fas ligand and caspase-3-mediated apoptosis, normalized the expression of TGF-beta1 and prevented cytokine-induced increase in glucose uptake into the cell. CB₁R inhibition with rimonabant showed similar protective properties as the CB₂R agonist JWH133, but to a lesser extent. In conclusion, CB₁R and CB₂R exert opposite effects on cell glucose uptake, proteolysis and apoptosis in both VSMCs and H9c2 cells. The CB₂R agonist JWH133 demonstrated the highest protective properties. These findings may pave the way to a new treatment of cardiovascular diseases, especially those associated with extracellular matrix degradation. Full article

(This article belongs to the Special Issue Therapeutic Potential for Cannabis and Cannabinoids)

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17 pages, 1653 KiB

Open AccessArticle

Safety and Tolerability of Oral Cannabinoids in People Living with HIV on Long-Term ART: A Randomized, Open-Label, Interventional Pilot Clinical Trial (CTNPT 028)

by Ralph-Sydney Mboumba Bouassa, Judy Needham, Dana Nohynek, Joel Singer, Terry Lee, Florian Bobeuf, Suzanne Samarani, Lina Del Balso, Natalie Paisible, Claude Vertzagias, Giada Sebastiani, Shari Margolese, Enrico Mandarino, Marina Klein, Bertrand Lebouché, Joseph Cox, Marie-Josée Brouillette, Jean-Pierre Routy, Jason Szabo, Réjean Thomas, Emmanuel Huchet, Antonio Vigano, Mohammad-Ali Jenabian and Cecilia T Costiniuk Show full author list Hide full author list

Biomedicines 2022, 10(12), 3168; https://doi.org/10.3390/biomedicines10123168 - 7 Dec 2022

Cited by 8 | Viewed by 3327

Abstract

Background: With anti-inflammatory properties, cannabinoids may be a potential strategy to reduce immune activation in people living with HIV (PLWH) but more information on their safety and tolerability is needed. Methods: We conducted an open-label interventional pilot study at the McGill University Health [...] Read more.

Background: With anti-inflammatory properties, cannabinoids may be a potential strategy to reduce immune activation in people living with HIV (PLWH) but more information on their safety and tolerability is needed. Methods: We conducted an open-label interventional pilot study at the McGill University Health Centre in Montreal, Canada. PLWH were randomized to oral Δ9-tetrahydrocannabinol (THC): cannabidiol (CBD) combination (THC 2.5 mg/CBD 2.5 mg) or CBD-only capsules (CBD 200 mg). Individuals titrated doses as tolerated to a maximum daily dose THC 15 mg/CBD 15 mg or 800 mg CBD, respectively, for 12 weeks. The primary outcome was the percentage of participants without any significant toxicity based on the WHO toxicity scale (Grades 0–2 scores). Results: Out of ten individuals, eight completed the study. Two from the CBD-only arm were withdrawn for safety concerns: phlebotomy aggravating pre-existing anemia and severe hepatitis on 800 mg CBD with newly discovered pancreatic adenocarcinoma, respectively. Seven did not have any significant toxicity. Cannabinoids did not alter hematology/biochemistry profiles. CD4 count, CD4/CD8 ratio, and HIV suppression remained stable. Most adverse effects were mild-moderate. Conclusions: In PLWH, cannabinoids seem generally safe and well-tolerated, though larger studies are needed. Screening for occult liver pathology should be performed and hepatic enzymes monitored, especially with high CBD doses. Full article

(This article belongs to the Special Issue Therapeutic Potential for Cannabis and Cannabinoids)

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15 pages, 1328 KiB

Open AccessArticle

“Flower Power”: Controlled Inhalation of THC-Predominant Cannabis Flos Improves Health-Related Quality of Life and Symptoms of Chronic Pain and Anxiety in Eligible UK Patients

by Guillermo Moreno-Sanz, Alvaro Madiedo, Michael Lynskey and Matthew R. D. Brown

Biomedicines 2022, 10(10), 2576; https://doi.org/10.3390/biomedicines10102576 - 14 Oct 2022

Cited by 11 | Viewed by 8799

Abstract

In November 2018, the UK’s Home Office established a legal route for eligible patients to be prescribed cannabis-based products for medicinal use in humans (CBPMs) as unlicensed medicines. These include liquid cannabis extracts for oral administration (“oils”) and dried flowers for inhalation (“flos”). [...] Read more.

In November 2018, the UK’s Home Office established a legal route for eligible patients to be prescribed cannabis-based products for medicinal use in humans (CBPMs) as unlicensed medicines. These include liquid cannabis extracts for oral administration (“oils”) and dried flowers for inhalation (“flos”). Smoking of CBPMs is expressly prohibited. To date, THC-predominant cannabis flowers remain the most prescribed CBPMs in project Twenty21 (T21), the first multi-center, prospective, observational UK cannabis patient registry. This observational, prospective data review analyzes patient-reported outcome measures (PROMS) collected by T21 associated with the inhalation of KHIRON 20/1, the most prescribed CBPM in the project. PROMS collected at baseline and at subsequent 3-month follow-up included health-related quality of life (HRQoL), general mood, and sleep. Condition-specific measures of illness severity were performed with the Brief Pain Inventory Short Form (BPI-SF) and the Generalized Anxiety Disorder 7-Item Scale (GAD-7). Participants (N = 344) were mostly males (77.6%, average age = 38.3) diagnosed mainly with chronic pain (50.9%) and anxiety-related disorders (25.3%). Inhalation of KHIRON 20/1 was associated with a marked increase in self-reported HRQoL, general mood, and sleep (N = 344; p < 0.001). Condition-specific assessments showed significant improvements in pain severity (T = 6.67; p < 0.001) and interference (T = 7.19; p < 0.001) in patients using KHIRON 20/1 for chronic pain (N = 174). Similar results were found for patients diagnosed with anxiety-related disorders (N = 107; T = 12.9; p < 0.001). Our results indicate that controlled inhalation of pharmaceutical grade, THC-predominant cannabis flos is associated with a significant improvement in patient-reported pain scores, mood, anxiety, sleep disturbances and overall HRQoL in a treatment-resistant clinical population. Full article

(This article belongs to the Special Issue Therapeutic Potential for Cannabis and Cannabinoids)

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9 pages, 1129 KiB

Open AccessArticle

Combinations of Cannabidiol and Δ⁹-Tetrahydrocannabinol in Reducing Chemotherapeutic Induced Neuropathic Pain

by Diana E. Sepulveda, Kent E. Vrana, Nicholas M. Graziane and Wesley M. Raup-Konsavage

Biomedicines 2022, 10(10), 2548; https://doi.org/10.3390/biomedicines10102548 - 12 Oct 2022

Cited by 12 | Viewed by 3897

Abstract

Neuropathic pain is a condition that impacts a substantial portion of the population and is expected to affect a larger percentage in the future. This type of pain is poorly managed by current therapies, including opioids and NSAIDS, and novel approaches are needed. [...] Read more.

Neuropathic pain is a condition that impacts a substantial portion of the population and is expected to affect a larger percentage in the future. This type of pain is poorly managed by current therapies, including opioids and NSAIDS, and novel approaches are needed. We used a cisplatin-induced model of neuropathic pain in mice to assess the effects of the cannabinoids THC and CBD alone or in varying ratios as anti-nociceptive agents. In addition to testing pure compounds, we also tested extracts containing high THC or CBD at the same ratios. We found that pure CBD had little impact on mechanical hypersensitivity, whereas THC reduced mechanical hypersensitivity in both male and female mice (as has been reported in the literature). Interestingly, we found that high CBD cannabis extract, at the same CBD dose as pure CBD, was able to reduce mechanical hypersensitivity, although not to the same level as high THC extract. These data suggest that, at least for CBD-dominant cannabis extracts, there is an increase in the anti-nociceptive activity that may be attributed to other constitutes of the plant. We also found that high THC extract or pure THC is the most efficacious treatment for reducing neuropathic pain in this model. Full article

(This article belongs to the Special Issue Therapeutic Potential for Cannabis and Cannabinoids)

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16 pages, 6375 KiB

Open AccessArticle

Single and Repeated Exposure to Cannabidiol Differently Modulate BDNF Expression and Signaling in the Cortico-Striatal Brain Network

by Francesca Mottarlini, Marco Fumagalli, Fernando Castillo-Díaz, Stefano Piazza, Giorgia Targa, Enrico Sangiovanni, Barbara Pacchetti, Mikael H. Sodergren, Mario Dell’Agli, Fabio Fumagalli and Lucia Caffino

Biomedicines 2022, 10(8), 1853; https://doi.org/10.3390/biomedicines10081853 - 1 Aug 2022

Cited by 8 | Viewed by 3072

Abstract

Cannabidiol (CBD) is a phytocannabinoid contained in the Cannabis sativa plant, devoid of psychotomimetic effects but with a broad-spectrum pharmacological activity. Because of its pharmacological profile and its ability to counteract the psychoactive Δ⁹-tetrahydrocannabinol (Δ9THC), CBD may be a potential treatment [...] Read more.

Cannabidiol (CBD) is a phytocannabinoid contained in the Cannabis sativa plant, devoid of psychotomimetic effects but with a broad-spectrum pharmacological activity. Because of its pharmacological profile and its ability to counteract the psychoactive Δ⁹-tetrahydrocannabinol (Δ9THC), CBD may be a potential treatment for several psychiatric and neurodegenerative disorders. In this study, we performed a dose−response evaluation of CBD modulatory effects on BDNF, a neurotrophin subserving pleiotropic effects on the brain, focusing on the cortico-striatal pathway for its unique role in the brain trafficking of BDNF. Male adult rats were exposed to single and repeated CBD treatments at different dosing regimen (5, 15, and 30 mg/kg), to investigate the rapid modulation of the neurotrophin (1 h after the single treatment) as well as a potential drug-free time point (24 h after the repeated treatment). We show here, for the first time, that CBD can be found in the rat brain and, specifically, in the medial prefrontal cortex (mPFC) following single or repeated exposure. In fact, we found that CBD is present in the mPFC of rats treated either acutely or repeatedly with the phytocannabinoid, with a clear dose−response profile. From a molecular standpoint, we found that single, but not repeated, CBD exposure upregulates BDNF in the mPFC, while the repeated exposure increased BDNF only in the striatum, with a slight decrease in the mPFC. Together, these data reveal a CBD dose-dependent and anatomically specific modulation of BDNF, which may be functionally relevant and may represent an added value for CBD as a supplement. Full article

(This article belongs to the Special Issue Therapeutic Potential for Cannabis and Cannabinoids)

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18 pages, 2442 KiB

Open AccessArticle

Anticonvulsant Action and Long-Term Effects of Chronic Cannabidiol Treatment in the Rat Pentylenetetrazole-Kindling Model of Epilepsy

by Zsolt Gáll, Krisztina Kelemen, Andrea Tolokán, István Zolcseak, István Sável, Réka Bod, Elek Ferencz, Szende Vancea, Melinda Urkon and Melinda Kolcsár

Biomedicines 2022, 10(8), 1811; https://doi.org/10.3390/biomedicines10081811 - 28 Jul 2022

Cited by 13 | Viewed by 3115

Abstract

Cannabidiol (CBD) showed anticonvulsant action in several preclinical models and is currently approved by regulatory agencies to treat childhood epilepsy syndromes. However, CBD treatment has limited benefits, and its long-term effects on cognition are not fully understood yet. This study aimed to examine [...] Read more.

Cannabidiol (CBD) showed anticonvulsant action in several preclinical models and is currently approved by regulatory agencies to treat childhood epilepsy syndromes. However, CBD treatment has limited benefits, and its long-term effects on cognition are not fully understood yet. This study aimed to examine the impact of long-term CBD treatment in the pentylenetetrazole (PTZ)-kindling model of epilepsy. Adult male Wistar rats (N = 24) received PTZ (35 mg/kg intraperitoneally) every other day until two consecutive generalized seizures occurred. CBD (60 mg/kg body weight) was administered daily by the oral route until the kindled state was achieved (n = 12). To confirm that the formulation and administration techniques were not of concern, liquid chromatography–mass spectrometry was performed to test the brain penetration of the CBD formula. As a result of CBD treatment, a lower mortality rate and significantly prolonged generalized seizure latency (925.3 ± 120.0 vs. 550.1 ± 69.62 s) were observed, while the frequency and duration of generalized seizures were not influenced. The CBD-treated group showed a significant decrease in vertical exploration in the open field test and a significant decrease in the discrimination index in the novel object recognition (NOR) test (−0.01 ± 0.17 vs. 0.57 ± 0.15, p = 0.04). The observed behavioral characteristics may be connected to the decreased thickness of the stratum pyramidale or the decreased astrogliosis observed in the hippocampus. In conclusion, CBD treatment did not prevent kindling, nor did it affect seizure frequency or duration. However, it did increase the latency to the first seizure and decreased the prolonged status epilepticus-related mortality in PTZ-kindled rats. The cognitive impairment observed in the NOR test may be related to the high dose used in this study, which may warrant further investigation. Full article

(This article belongs to the Special Issue Therapeutic Potential for Cannabis and Cannabinoids)

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17 pages, 3276 KiB

Open AccessArticle

Differential Effects of D9 Tetrahydrocannabinol (THC)- and Cannabidiol (CBD)-Based Cannabinoid Treatments on Macrophage Immune Function In Vitro and on Gastrointestinal Inflammation in a Murine Model

by Zhanna Yekhtin, Iman Khuja, David Meiri, Reuven Or and Osnat Almogi-Hazan

Biomedicines 2022, 10(8), 1793; https://doi.org/10.3390/biomedicines10081793 - 26 Jul 2022

Cited by 20 | Viewed by 3524

Abstract

Phytocannabinoids possess a wide range of immune regulatory properties, mediated by the endocannabinoid system. Monocyte/macrophage innate immune cells express endocannabinoid receptors. Dysregulation of macrophage function is involved in the pathogenesis of different inflammatory diseases, including inflammatory bowel disease. In our research, we aimed [...] Read more.

Phytocannabinoids possess a wide range of immune regulatory properties, mediated by the endocannabinoid system. Monocyte/macrophage innate immune cells express endocannabinoid receptors. Dysregulation of macrophage function is involved in the pathogenesis of different inflammatory diseases, including inflammatory bowel disease. In our research, we aimed to evaluate the effects of the phytocannabinoids D9 tetrahydrocannabinol (THC) and cannabidiol (CBD) on macrophage activation. Macrophages from young and aged C57BL/6 mice were activated in vitro in the presence of pure cannabinoids or cannabis extracts. The phenotype of the cells, nitric oxide (NO•) secretion, and cytokine secretion were examined. In addition, these treatments were administered to murine colitis model. The clinical statuses of mice, levels of colon infiltrating macrophages, and inflammatory cytokines in the blood, were evaluated. We demonstrated inhibition of macrophage NO• and cytokine secretion and significant effects on expression of cell surface molecules. In the murine model, clinical scores were improved and macrophage colon infiltration reduced following treatment. We identified higher activity of cannabis extracts as compared with pure cannabinoids. Each treatment had a unique effect on cytokine composition. Overall, our results establish that the effects of cannabinoid treatments differ. A better understanding of the reciprocal relationship between cannabinoids and immunity is essential to design targeted treatment strategies. Full article

(This article belongs to the Special Issue Therapeutic Potential for Cannabis and Cannabinoids)

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26 pages, 3395 KiB

Open AccessArticle

Enhancing Endocannabinoid Signaling via β-Catenin in the Nucleus Accumbens Attenuates PTSD- and Depression-like Behavior of Male Rats

by Tomer Mizrachi Zer-Aviv, Larglinda Islami, Peter J. Hamilton, Eric M. Parise, Eric J. Nestler, Brenda Sbarski and Irit Akirav

Biomedicines 2022, 10(8), 1789; https://doi.org/10.3390/biomedicines10081789 - 25 Jul 2022

Cited by 10 | Viewed by 2651

Abstract

Inhibition of fatty acid amide hydrolase (FAAH), which increases anandamide levels, has been suggested as a potential treatment for stress-related conditions. We examined whether the stress-preventing effects of the FAAH inhibitor URB597 on behavior are mediated via β-catenin in the nucleus accumbens (NAc). [...] Read more.

Inhibition of fatty acid amide hydrolase (FAAH), which increases anandamide levels, has been suggested as a potential treatment for stress-related conditions. We examined whether the stress-preventing effects of the FAAH inhibitor URB597 on behavior are mediated via β-catenin in the nucleus accumbens (NAc). Male rats were exposed to the shock and reminders model of PTSD and then treated with URB597 (0.4 mg/kg; i.p.). They were tested for anxiety- (freezing, startle response), depression-like behaviors (despair, social preference, anhedonia), and memory function (T-maze, social recognition). We also tested the involvement of the CB1 receptor (CB1r), β-catenin, and metabotropic glutamate receptor subtype 5 (mGluR5) proteins. URB597 prevented the shock- and reminders-induced increase in anxiety- and depressive-like behaviors, as well as the impaired memory via the CB1r-dependent mechanism. In the NAc, viral-mediated β-catenin overexpression restored the behavior of rats exposed to stress and normalized the alterations in protein levels in the NAc and the prefrontal cortex. Importantly, when NAc β-catenin levels were downregulated by viral-mediated gene transfer, the therapeutic-like effects of URB597 were blocked. We suggest a potentially novel mechanism for the therapeutic-like effects of FAAH inhibition that is dependent on β-catenin activation in the NAc in a PTSD rat model. Full article

(This article belongs to the Special Issue Therapeutic Potential for Cannabis and Cannabinoids)

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14 pages, 1202 KiB

Open AccessArticle

A Placebo-Controlled Trial of Cannabinoid Treatment for Disruptive Behavior in Children and Adolescents with Autism Spectrum Disorder: Effects on Sleep Parameters as Measured by the CSHQ

by Aviad Schnapp, Moria Harel, Dalit Cayam-Rand, Hanoch Cassuto, Lola Polyansky and Adi Aran

Biomedicines 2022, 10(7), 1685; https://doi.org/10.3390/biomedicines10071685 - 13 Jul 2022

Cited by 13 | Viewed by 4832

Abstract

Autism spectrum disorder (ASD) is often associated with debilitating sleep disturbances. While anecdotal evidence suggests the positive effect of cannabinoids, randomized studies are lacking. Here, we report the effects of cannabinoid treatment on the sleep of 150 children and adolescents with ASD, as [...] Read more.

Autism spectrum disorder (ASD) is often associated with debilitating sleep disturbances. While anecdotal evidence suggests the positive effect of cannabinoids, randomized studies are lacking. Here, we report the effects of cannabinoid treatment on the sleep of 150 children and adolescents with ASD, as part of a double-blind, placebo-controlled study that assessed the impact of cannabinoid treatment on behavior (NCT02956226). Participants were randomly assigned to one of the following three treatments: (1) whole-plant cannabis extract, containing cannabidiol (CBD) and Δ9-Tetrahydrocannabinol (THC) in a 20:1 ratio, (2) purified CBD and THC extract in the same ratio, and (3) an oral placebo. After 12 weeks of treatment (Period 1) and a 4-week washout period, participants crossed over to a predetermined, second 12-week treatment (Period 2). Sleep disturbances were assessed using the Children’s Sleep-Habit Questionnaire (CSHQ). We found that the CBD-rich cannabinoid treatment was not superior to the placebo treatment in all aspects of sleep measured by the CSHQ, including bedtime resistance, sleep-onset delay, and sleep duration. Notably, regardless of the treatment (cannabinoids or placebo), improvements in the CSHQ total score were associated with improvements in the autistic core symptoms, as indicated by the Social Responsiveness Scale total scores (Period 1: r = 0.266, p = 0.008; Period 2: r = 0.309, p = 0.004). While this study failed to demonstrate that sleep improvements were higher with cannabinoids than they were with the placebo treatment, further studies are required. Full article

(This article belongs to the Special Issue Therapeutic Potential for Cannabis and Cannabinoids)

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12 pages, 423 KiB

Open AccessArticle

Serum Concentrations of the Endocannabinoid, 2-Arachidonoylglycerol, in the Peri-Trauma Period Are Positively Associated with Chronic Pain Months Later

by Colleen M. Trevino, Cecilia J. Hillard, Aniko Szabo and Terri A. deRoon-Cassini

Biomedicines 2022, 10(7), 1599; https://doi.org/10.3390/biomedicines10071599 - 5 Jul 2022

Cited by 2 | Viewed by 1852

Abstract

Endocannabinoid signaling and the hypothalamic-pituitary-adrenal axis are activated by trauma and both stress systems regulate the transition from acute to chronic pain. This study aimed to develop a model of relationships among circulating concentrations of cortisol and endocannabinoids (eCBs) immediately after traumatic injury [...] Read more.

Endocannabinoid signaling and the hypothalamic-pituitary-adrenal axis are activated by trauma and both stress systems regulate the transition from acute to chronic pain. This study aimed to develop a model of relationships among circulating concentrations of cortisol and endocannabinoids (eCBs) immediately after traumatic injury and the presence of chronic pain months later. Pain scores and serum concentrations of eCBs and cortisol were measured during hospitalization and 5–10 months later in 147 traumatically injured individuals. Exploratory correlational analyses and path analysis were completed. The study sample was 50% Black and Latino and primarily male (69%); 34% percent endorsed a pain score of 4 or greater at follow-up and were considered to have chronic pain. Path analysis was used to model relationships among eCB, 2-arachidonolyglycerol (2-AG), cortisol, and pain, adjusting for sex and injury severity (ISS). Serum 2-AG concentrations at the time of injury were associated with chronic pain in 3 ways: a highly significant, independent positive predictor; a mediator of the effect of ISS, and through a positive relationship with cortisol concentrations. These data indicate that 2-AG concentrations at the time of an injury are positively associated with chronic pain and suggest excessive activation of endocannabinoid signaling contributes to risk for chronic pain. Full article

(This article belongs to the Special Issue Therapeutic Potential for Cannabis and Cannabinoids)

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15 pages, 1833 KiB

Open AccessArticle

Anti-Tumorigenic Effect of a Novel Derivative of 2-Hydroxyoleic Acid and the Endocannabinoid Anandamide on Neuroblastoma Cells

by Hana Golan, Raphael Mechoulam, Reem Smoum, Efrat Cohen-Zada, Sara Pri-Chen, Sapir Wiener, Igor Grinberg, Dekel D. Bar-Lev, Christeeneh G. Haj, Tamar Fisher and Amos Toren

Biomedicines 2022, 10(7), 1552; https://doi.org/10.3390/biomedicines10071552 - 29 Jun 2022

Cited by 1 | Viewed by 2786

Abstract

Modulation of the endogenous cannabinoid system has been suggested as a potential anticancer strategy. In the search for novel and less toxic therapeutic options, structural modifications of the endocannabinoid anandamide and the synthetic derivative of oleic acid, Minerval (HU-600), were done to obtain [...] Read more.

Modulation of the endogenous cannabinoid system has been suggested as a potential anticancer strategy. In the search for novel and less toxic therapeutic options, structural modifications of the endocannabinoid anandamide and the synthetic derivative of oleic acid, Minerval (HU-600), were done to obtain 2-hydroxy oleic acid ethanolamide (HU-585), which is an HU-600 derivative with the anandamide side chain. We showed that treatment of SK-N-SH neuroblastoma cells with HU-585 induced a better anti-tumorigenic effect in comparison to HU-600 as evidenced by 3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide assay, colony-forming assay, and migration assay. Moreover, HU-585 demonstrated pro-apoptotic properties shown by increased levels of activated caspase-3 following treatment and a better senescence induction effect in comparison to HU-600, as demonstrated by increased activity of lysosomal β-galactosidase. Finally, we observed that combined treatment of HU-585 with the senolytic drugs ABT-263 in vitro, and ABT-737 in vivo resulted in enhanced anti-proliferative effects and reduced neuroblastoma xenograft growth in comparison to treatment with HU-585 alone. Based on these results, we suggest that HU-585 is a pro-apoptotic and senescence-inducing compound, better than HU-600. Hence, it may be a beneficial option for the treatment of resistant neuroblastoma especially when combined with senolytic drugs that enhance its anti-tumorigenic effects. Full article

(This article belongs to the Special Issue Therapeutic Potential for Cannabis and Cannabinoids)

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14 pages, 2129 KiB

Open AccessArticle

Impact of Δ⁹-Tetrahydrocannabinol on Rheumatoid Arthritis Synovial Fibroblasts Alone and in Co-Culture with Peripheral Blood Mononuclear Cells

by Torsten Lowin, Christina Kok, Sophie Smutny and Georg Pongratz

Biomedicines 2022, 10(5), 1118; https://doi.org/10.3390/biomedicines10051118 - 11 May 2022

Cited by 5 | Viewed by 5110

Abstract

δ9-Tetrahydrocannabinol (THC) has demonstrated anti-inflammatory effects in animal models of arthritis, but its mechanism of action and cellular targets are still unclear. The purpose of this study is to elucidate the effects of THC (0.1–25 µM) on synovial fibroblasts from patients with rheumatoid [...] Read more.

δ9-Tetrahydrocannabinol (THC) has demonstrated anti-inflammatory effects in animal models of arthritis, but its mechanism of action and cellular targets are still unclear. The purpose of this study is to elucidate the effects of THC (0.1–25 µM) on synovial fibroblasts from patients with rheumatoid arthritis (RASF) and peripheral blood mononuclear cells (PBMC) from healthy donors in respect to proliferation, calcium mobilization, drug uptake, cytokine and immunoglobulin production. Intracellular calcium and drug uptake were determined by fluorescent dyes Cal-520 and PoPo3, respectively. Cytokine and immunoglobulin production were evaluated by ELISA. Cannabinoid receptors 1 and 2 (CB₁ and CB₂) were detected by flow cytometry. RASF express CB₁ and CB₂ and the latter was increased by tumor necrosis factor (TNF). In RASF, THC (≥5 µM) increased intracellular calcium levels/PoPo3 uptake in a TRPA1-dependent manner and reduced interleukin-8 (IL-8) and matrix metalloprotease 3 (MMP-3) production at high concentrations (25 µM). Proliferation was slightly enhanced at intermediate THC concentrations (1–10 µM) but was completely abrogated at 25 µM. In PBMC alone, THC decreased interleukin-10 (IL-10) production and increased immunoglobulin G (IgG). In PBMC/RASF co-culture, THC decreased TNF production when cells were stimulated with interferon-γ (IFN-γ) or CpG. THC provides pro- and anti-inflammatory effects in RASF and PBMC. This is dependent on the activating stimulus and concentration of THC. Therefore, THC might be used to treat inflammation in RA but it might need titrating to determine the effective concentration. Full article

(This article belongs to the Special Issue Therapeutic Potential for Cannabis and Cannabinoids)

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Review

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19 pages, 1601 KiB

Open AccessReview

The Endocannabinoid System as a Target for Neuroprotection/Neuroregeneration in Perinatal Hypoxic–Ischemic Brain Injury

by Andrea Duranti, Gorane Beldarrain, Antonia Álvarez, Matilde Sbriscia, Silvia Carloni, Walter Balduini and Daniel Alonso-Alconada

Biomedicines 2023, 11(1), 28; https://doi.org/10.3390/biomedicines11010028 - 22 Dec 2022

Cited by 6 | Viewed by 2893

Abstract

The endocannabinoid (EC) system is a complex cell-signaling system that participates in a vast number of biological processes since the prenatal period, including the development of the nervous system, brain plasticity, and circuit repair. This neuromodulatory system is also involved in the response [...] Read more.

The endocannabinoid (EC) system is a complex cell-signaling system that participates in a vast number of biological processes since the prenatal period, including the development of the nervous system, brain plasticity, and circuit repair. This neuromodulatory system is also involved in the response to endogenous and environmental insults, being of special relevance in the prevention and/or treatment of vascular disorders, such as stroke and neuroprotection after neonatal brain injury. Perinatal hypoxia–ischemia leading to neonatal encephalopathy is a devastating condition with no therapeutic approach apart from moderate hypothermia, which is effective only in some cases. This overview, therefore, gives a current description of the main components of the EC system (including cannabinoid receptors, ligands, and related enzymes), to later analyze the EC system as a target for neonatal neuroprotection with a special focus on its neurogenic potential after hypoxic–ischemic brain injury. Full article

(This article belongs to the Special Issue Therapeutic Potential for Cannabis and Cannabinoids)

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24 pages, 1885 KiB

Open AccessReview

Secondary Terpenes in Cannabis sativa L.: Synthesis and Synergy

by Francisco T. Chacon, Wesley M. Raup-Konsavage, Kent E. Vrana and Joshua J. Kellogg

Biomedicines 2022, 10(12), 3142; https://doi.org/10.3390/biomedicines10123142 - 6 Dec 2022

Cited by 12 | Viewed by 7470

Abstract

Cannabis is a complex biosynthetic plant, with a long history of medicinal use. While cannabinoids have received the majority of the attention for their psychoactive and pharmacological activities, cannabis produces a diverse array of phytochemicals, such as terpenes. These compounds are known to [...] Read more.

Cannabis is a complex biosynthetic plant, with a long history of medicinal use. While cannabinoids have received the majority of the attention for their psychoactive and pharmacological activities, cannabis produces a diverse array of phytochemicals, such as terpenes. These compounds are known to play a role in the aroma and flavor of cannabis but are potent biologically active molecules that exert effects on infectious as well as chronic diseases. Furthermore, terpenes have the potential to play important roles, such as synergistic and/or entourage compounds that modulate the activity of the cannabinoids. This review highlights the diversity and bioactivities of terpenes in cannabis, especially minor or secondary terpenes that are less concentrated in cannabis on a by-mass basis. We also explore the question of the entourage effect in cannabis, which studies to date have supported or refuted the concept of synergy in cannabis, and where synergy experimentation is headed, to better understand the interplay between phytochemicals within Cannabis sativa L. Full article

(This article belongs to the Special Issue Therapeutic Potential for Cannabis and Cannabinoids)

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49 pages, 4614 KiB

Open AccessReview

The Therapeutic Potential of the Endocannabinoid System in Age-Related Diseases

by Ivona Maria Tudorancea, Mitică Ciorpac, Gabriela Dumitrița Stanciu, Cătălin Caratașu, Alina Săcărescu, Bogdan Ignat, Alexandra Burlui, Elena Rezuș, Ioana Creangă, Teodora Alexa-Stratulat, Ionuț Tudorancea and Bogdan Ionel Tamba

Biomedicines 2022, 10(10), 2492; https://doi.org/10.3390/biomedicines10102492 - 6 Oct 2022

Cited by 8 | Viewed by 5550

Abstract

The endocannabinoid system (ECS) dynamically regulates many aspects of mammalian physiology. ECS has gained substantial interest since growing evidence suggests that it also plays a major role in several pathophysiological conditions due to its ability to modulate various underlying mechanisms. Furthermore, cannabinoids, as [...] Read more.

The endocannabinoid system (ECS) dynamically regulates many aspects of mammalian physiology. ECS has gained substantial interest since growing evidence suggests that it also plays a major role in several pathophysiological conditions due to its ability to modulate various underlying mechanisms. Furthermore, cannabinoids, as components of the cannabinoid system (CS), have proven beneficial effects such as anti-inflammatory, immunomodulatory, neuromodulatory, antioxidative, and cardioprotective effects. In this comprehensive review, we aimed to describe the complex interaction between CS and most common age-related diseases such as neuro-degenerative, oncological, skeletal, and cardiovascular disorders, together with the potential of various cannabinoids to ameliorate the progression of these disorders. Since chronic inflammation is postulated as the pillar of all the above-mentioned medical conditions, we also discuss in this paper the potential of CS to ameliorate aging-associated immune system dysregulation. Full article

(This article belongs to the Special Issue Therapeutic Potential for Cannabis and Cannabinoids)

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48 pages, 2879 KiB

Open AccessReview

Anti-Microbial Activity of Phytocannabinoids and Endocannabinoids in the Light of Their Physiological and Pathophysiological Roles

by Ronit Vogt Sionov and Doron Steinberg

Biomedicines 2022, 10(3), 631; https://doi.org/10.3390/biomedicines10030631 - 9 Mar 2022

Cited by 23 | Viewed by 5126

Abstract

Antibiotic resistance has become an increasing challenge in the treatment of various infectious diseases, especially those associated with biofilm formation on biotic and abiotic materials. There is an urgent need for new treatment protocols that can also target biofilm-embedded bacteria. Many secondary metabolites [...] Read more.

Antibiotic resistance has become an increasing challenge in the treatment of various infectious diseases, especially those associated with biofilm formation on biotic and abiotic materials. There is an urgent need for new treatment protocols that can also target biofilm-embedded bacteria. Many secondary metabolites of plants possess anti-bacterial activities, and especially the phytocannabinoids of the Cannabis sativa L. varieties have reached a renaissance and attracted much attention for their anti-microbial and anti-biofilm activities at concentrations below the cytotoxic threshold on normal mammalian cells. Accordingly, many synthetic cannabinoids have been designed with the intention to increase the specificity and selectivity of the compounds. The structurally unrelated endocannabinoids have also been found to have anti-microbial and anti-biofilm activities. Recent data suggest for a mutual communication between the endocannabinoid system and the gut microbiota. The present review focuses on the anti-microbial activities of phytocannabinoids and endocannabinoids integrated with some selected issues of their many physiological and pharmacological activities. Full article

(This article belongs to the Special Issue Therapeutic Potential for Cannabis and Cannabinoids)

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Other

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13 pages, 4280 KiB

Open AccessBrief Report

Impaired Ghrelin Signaling Does Not Lead to Alterations of Anxiety-like Behaviors in Adult Mice Chronically Exposed to THC during Adolescence

by Matija Sestan-Pesa, Marya Shanabrough, Tamas L. Horvath and Maria Consolata Miletta

Biomedicines 2023, 11(1), 144; https://doi.org/10.3390/biomedicines11010144 - 6 Jan 2023

Cited by 3 | Viewed by 2270

Abstract

As marijuana use during adolescence has been increasing, the need to understand the effects of its long-term use becomes crucial. Previous research suggested that marijuana consumption during adolescence increases the risk of developing mental illnesses, such as schizophrenia, depression, and anxiety. Ghrelin is [...] Read more.

As marijuana use during adolescence has been increasing, the need to understand the effects of its long-term use becomes crucial. Previous research suggested that marijuana consumption during adolescence increases the risk of developing mental illnesses, such as schizophrenia, depression, and anxiety. Ghrelin is a peptide produced primarily in the gut and is important for feeding behavior. Recent studies have shown that ghrelin and its receptor, the growth hormone secretagogue receptor (GHSR), play important roles in mediating stress, as well as anxiety and depression-like behaviors in animal models. Here, we investigated the effects of chronic tetrahydrocannabinol (THC) administration during late adolescence (P42–55) in GHSR (GHSR ^−/−) knockout mice and their wild-type littermates in relation to anxiety-like behaviors. We determined that continuous THC exposure during late adolescence did not lead to any significant alterations in the anxiety-like behaviors of adult mice, regardless of genotype, following a prolonged period of no exposure (1 month). These data indicate that in the presence of intact or impaired ghrelin/GHSR signaling, THC exposure during late adolescence has limited if any long-term impact on anxiety-like behaviors in mice. Full article

(This article belongs to the Special Issue Therapeutic Potential for Cannabis and Cannabinoids)

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28 pages, 1911 KiB

Open AccessSystematic Review

A Review on the Bioactivity of Cannabinoids on Zebrafish Models: Emphasis on Neurodevelopment

by Rosario Licitra, Maria Marchese, Valentina Naef, Asahi Ogi, Marco Martinelli, Claudia Kiferle, Baldassare Fronte and Filippo Maria Santorelli

Biomedicines 2022, 10(8), 1820; https://doi.org/10.3390/biomedicines10081820 - 28 Jul 2022

Cited by 6 | Viewed by 2974

Abstract

For centuries, the cannabis plant has been used as a source of food, fiber, and medicine. Recently, scientific interest in cannabis has increased considerably, as its bioactive compounds have shown promising potential in the treatment of numerous musculoskeletal and neurological diseases in humans. [...] Read more.

For centuries, the cannabis plant has been used as a source of food, fiber, and medicine. Recently, scientific interest in cannabis has increased considerably, as its bioactive compounds have shown promising potential in the treatment of numerous musculoskeletal and neurological diseases in humans. However, the mechanisms that underlie its possible effects on neurodevelopment and nervous-system functioning remain poorly understood and need to be further investigated. Although the bulk of research on cannabis and cannabinoids is based on in vitro or rodent models, the zebrafish has now emerged as a powerful in vivo model for drug-screening studies and translational research. We here review the available literature on the use of cannabis/cannabinoids in zebrafish, and particularly in zebrafish models of neurological disorders. A critical analysis suggests that zebrafish could serve as an experimental tool for testing the bioactivity of cannabinoids, and they could thus provide important insights into the safety and efficacy of different cannabis-extract-based products. The review showed that zebrafish exhibit similar behaviors to rodents following cannabinoid exposure. The authors stress the importance of analyzing the full spectrum of naturally occurring cannabinoids, rather than just the main ones, THC and CBD, and they offer some pointers on performing behavioral analysis in zebrafish. Full article

(This article belongs to the Special Issue Therapeutic Potential for Cannabis and Cannabinoids)

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