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Biomedicines
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Therapeutic Potential for Cannabis and Cannabinoids
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Therapeutic Potential for Cannabis and Cannabinoids

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Molecular and Translational Medicine".

Deadline for manuscript submissions: closed (30 November 2022) | Viewed by 67570

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editor

Dr. Wesley M. Raup-Konsavage

E-Mail Website
Guest Editor
Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, PA, USA
Interests: cannabis; cancer; inflammatory bowel disease; pain; cannabinoids
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cannabis has a history of medical use dating back millennia; however, the use of cannabis for medicinal purposes fell out of favor in the middle of the last century. There is currently a renewed interest in the potential medicinal value of this plant, as well as individual compounds produced by Cannabis (as well as synthetic analogs). Currently, nearly 50 countries permit the medical use of cannabis, and over a dozen other countries have legalized cannabis-based products (CBD, Sativex, Dronabinol, etc.) for medical use. While there exists a plethora of anecdotal reports that cannabis can treat a variety of diseases, there is a limited amount of strong, evidence-based scientific data to support these claims. 

This Special Edition of Biomedicines, “Therapeutic Potential for Cannabis and Cannabinoids”, will be dedicated to providing evidence for the medicinal value of cannabis to treat human illness and disease. Topics will include but are not limited to preclinical animal models examining the efficacy of cannabis and cannabinoid derivatives on pain, anxiety, cancer, and other diseases; and cell and molecular models of cannabinoid pharmacokinetics, drug-drug interactions, and disease treatment. These studies will be of great importance not only for progressing the cannabis field, but also for validating the use of cannabis and cannabinoids as therapeutics.   

Dr. Wesley M. Raup-Konsavage
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomedicines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • cannabis
  • tetrahydrocannabinol (THC)
  • cannabidiol (CBD)
  • cannabigerol (CBG)
  • cannabinoid
  • cannabinol (CBN)
  • cannabichromene (CBC)
  • pain
  • cancer
  • anxiety
  • PTSD
  • sleep disorders
  • neuroprotection
  • anti-inflammatory

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Published Papers (21 papers)

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Editorial

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4 pages, 210 KiB  
Editorial
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 2058
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

Jump to: Editorial, Review, Other

10 pages, 236 KiB  
Article
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 - 08 Jan 2023
Cited by 3 | Viewed by 2407
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  
Article
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 1 | Viewed by 3124
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  
Article
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 2 | Viewed by 1509
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  
Article
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 Costiniukadd Show full author list remove Hide full author list
Biomedicines 2022, 10(12), 3168; https://doi.org/10.3390/biomedicines10123168 - 07 Dec 2022
Cited by 6 | Viewed by 2707
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  
Article
“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 8 | Viewed by 7309
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  
Article
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 7 | Viewed by 3280
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  
Article
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 - 01 Aug 2022
Cited by 6 | Viewed by 2410
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  
Article
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 9 | Viewed by 2395
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  
Article
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 11 | Viewed by 2844
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  
Article
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 8 | Viewed by 1854
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  
Article
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 8 | Viewed by 3844
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  
Article
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 - 05 Jul 2022
Cited by 1 | Viewed by 1474
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  
Article
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 2355
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  
Article
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 3 | Viewed by 4618
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  
Review
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 5 | Viewed by 2310
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  
Review
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 - 06 Dec 2022
Cited by 9 | Viewed by 5406
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  
Review
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 - 06 Oct 2022
Cited by 5 | Viewed by 4577
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  
Review
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 - 09 Mar 2022
Cited by 20 | Viewed by 4366
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

13 pages, 4280 KiB  
Brief 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 - 06 Jan 2023
Cited by 3 | Viewed by 1698
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  
Systematic 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 5 | Viewed by 2415
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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