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Gil B, Sullivan M, Scaife C, Glennon JC, Herron C. Cannabidiolic Acid Rescues Deficits in Hippocampal Long-Term Potentiation in Models of Alzheimer's Disease: An Electrophysiological and Proteomic Analysis. Int J Mol Sci 2025; 26:4944. [PMID: 40430085 DOI: 10.3390/ijms26104944] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2025] [Revised: 05/09/2025] [Accepted: 05/14/2025] [Indexed: 05/29/2025] Open
Abstract
In this study, we have examined the neuroprotective effects of cannabidiolic acid (CBDA) in models of Alzheimer's disease (AD). We used in vitro electrophysiological recording in hippocampal slices and performed proteomic analysis of cortical tissue from APPswe/PS1dE9 (APP/PS1) mice. In wild-type (WT) slices from C57BL6 mice, acute treatment with CBDA (10 μM) did not alter levels of hippocampal long-term potentiation (LTP); however, it did reverse the attenuation of LTP produced by acute beta amyloid peptide (Aβ42). We also examined the effects of CBDA or vehicle in APP/PS1 mice and WT littermates over a 5-week period at 8 months. LTP levels recorded in slices from WT mice treated with CBDA at 1, 10, or 30 mg/kg (IP) or vehicle were similar. LTP was attenuated in slices from vehicle-treated APP/PS1 compared to vehicle-treated WT mice, while treatment of APP/PS1 mice with all doses of CBDA reversed the deficits in LTP. There was also a deficit in paired-pulse facilitation (PPF) in vehicle-treated APP/PS1 compared to WT, indicating altered synaptic function and transmitter release; this was reversed in slices from CBDA-treated APP/PS1 mice. Levels of cortical soluble Aβ42 were similar across CBDA- and vehicle-treated groups; however, the level of aggregated Aβ42 was decreased in the CBDA-treated group. Proteomic analysis of cortical tissue from APP/PS1 cortex compared to WT revealed alterations in protein expression, with pathway enrichment analyses suggesting implicated canonical pathways, including mitochondrial dysfunction, protein sorting, and synaptogenesis; all were significantly improved by CBDA treatment. These changes likely facilitate the improvement in synaptic transmission and LTP we observed following CBDA treatment in APP/PS1 mice. This research suggests that CBDA should be considered a novel therapy for AD.
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Affiliation(s)
- Beatriz Gil
- School of Biomolecular and Biomedical Sciences, University College Dublin, Conway Institute, Dublin 4, Ireland
| | - Mairéad Sullivan
- School of Medicine and Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Conway Institute, Dublin 4, Ireland
| | | | - Jeffrey C Glennon
- School of Medicine and Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Conway Institute, Dublin 4, Ireland
| | - Caroline Herron
- School of Biomolecular and Biomedical Sciences, University College Dublin, Conway Institute, Dublin 4, Ireland
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2
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Tran J, Dimech AM, Vassiliadis S, Elkins AC, Cogan NOI, Naim-Feil E, Rochfort SJ. Determination of Optimal Harvest Time in Cannabis sativa L. Based upon Stigma Color Transition. PLANTS (BASEL, SWITZERLAND) 2025; 14:1532. [PMID: 40431097 DOI: 10.3390/plants14101532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/08/2025] [Revised: 05/06/2025] [Accepted: 05/06/2025] [Indexed: 05/29/2025]
Abstract
Cannabis sativa L. is cultivated for therapeutic and recreational use. Delta-9 tetrahydrocannabinol (THC) and cannabidiol (CBD) are primarily responsible for its psychoactive and medicinal effects. As the global cannabis industry continues to expand, constant review and optimization of horticultural practices are needed to ensure a reliable harvest and improved crop quality. There is currently uncertainty about the optimal harvest time of C. sativa, i.e., when cannabinoid concentrations are at their highest during inflorescence maturation. At present, growers observe the color transition of stigmas from white to amber as an indicator of harvest time. This research investigates the relationship between stigma color and cannabinoid concentration using liquid chromatography-mass spectrometry (LCMS) and digital image analysis. Additionally, early screening prediction models have also been developed for six cannabinoids using near-infrared (NIR) spectroscopy and LCMS to assist in early cannabinoid determination. Among the genotypes grown, 22 of 25 showed cannabinoid concentration peaks between the third (mostly amber) and fourth (fully amber) stages; however, some genotypes peaked within the first (no amber) and second (some amber) stages. We have determined that the current 'rule of thumb' of harvesting when a cannabis plant is mostly amber is still a useful approximation in most cases; however, studies on individual genotypes should be performed to determine their individual optimal harvest time based on the desired cannabinoid profile or total cannabinoid concentration.
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Affiliation(s)
- Jonathan Tran
- Agriculture Victoria Research, Department of Energy, Environment and Climate Action, AgriBio Centre for Agribioscience, Bundoora, Melbourne, VIC 3083, Australia
| | - Adam M Dimech
- Agriculture Victoria Research, Department of Energy, Environment and Climate Action, AgriBio Centre for Agribioscience, Bundoora, Melbourne, VIC 3083, Australia
| | - Simone Vassiliadis
- Agriculture Victoria Research, Department of Energy, Environment and Climate Action, AgriBio Centre for Agribioscience, Bundoora, Melbourne, VIC 3083, Australia
| | - Aaron C Elkins
- Agriculture Victoria Research, Department of Energy, Environment and Climate Action, AgriBio Centre for Agribioscience, Bundoora, Melbourne, VIC 3083, Australia
| | - Noel O I Cogan
- Agriculture Victoria Research, Department of Energy, Environment and Climate Action, AgriBio Centre for Agribioscience, Bundoora, Melbourne, VIC 3083, Australia
- School of Applied Systems Biology, La Trobe University, Bundoora, Melbourne, VIC 3083, Australia
| | - Erez Naim-Feil
- Agriculture Victoria Research, Department of Energy, Environment and Climate Action, AgriBio Centre for Agribioscience, Bundoora, Melbourne, VIC 3083, Australia
| | - Simone J Rochfort
- Agriculture Victoria Research, Department of Energy, Environment and Climate Action, AgriBio Centre for Agribioscience, Bundoora, Melbourne, VIC 3083, Australia
- School of Applied Systems Biology, La Trobe University, Bundoora, Melbourne, VIC 3083, Australia
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3
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Suriyawongpongsa P, Niyom S, Wanapinit K, Vijarnsorn M, Roytrakul S, Ploypetch S. Effects of Cannabidiol Oil on Anesthetic Requirements in Cats: MAC Determination and Serum Profiling via Nanoscale Liquid Chromatography-Tandem Mass Spectrometry. Animals (Basel) 2025; 15:1393. [PMID: 40427271 DOI: 10.3390/ani15101393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2025] [Revised: 05/06/2025] [Accepted: 05/09/2025] [Indexed: 05/29/2025] Open
Abstract
Cannabidiol (CBD), a non-psychotropic cannabinoid derived from Cannabis plants, is increasingly explored for its potential therapeutic applications in veterinary medicine. This study aimed to evaluate the impact of CBD oil on the minimum alveolar concentration of isoflurane (MACiso) in cats. Sixteen healthy cats underwent isoflurane anesthesia, and the MACiso was determined using the tail-clamping technique both at baseline and 30 min after the administration of CBD oil (2 mg/kg) via a stomach tube. CBD administration resulted in a significant 11% reduction in the MACiso, from 1.77 ± 0.14% to 1.62 ± 0.21% (p < 0.001). Following CBD administration, heart and respiratory rates were elevated at the time of MACiso determination compared to baseline whereas other physiological parameters remained unchanged. Serum biochemical analysis conducted two weeks post administration revealed a significant decrease in blood urea nitrogen (BUN) levels while one cat exhibited a mild increase in alanine aminotransferase (ALT). Proteomic analysis identified 12 CBD-associated proteins in feline serum 30 min post administration, with CBDA and THCA synthases demonstrating significant upregulation. These findings indicate that CBD oil reduces anesthetic requirements in cats without inducing significant physiological disturbances. Further research is warranted to elucidate the underlying mechanisms of CBD's anesthetic-sparing effects and its implications in veterinary anesthesia.
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Affiliation(s)
- Panisara Suriyawongpongsa
- Veterinary Clinical Studies Program, Faculty of Veterinary Medicine, Graduated School, Kasetsart University, Nakorn Pathom 73140, Thailand
| | - Sirirat Niyom
- Department of Companion Animal Clinical Sciences, Faculty of Veterinary Medicine, Kasetsart University, Bangkok 10900, Thailand
| | - Kannika Wanapinit
- Kasetsart University Veterinary Teaching Hospital, Faculty of Veterinary Medicine, Kasetsart University, Bangkok 10900, Thailand
| | - Monchanok Vijarnsorn
- Department of Companion Animal Clinical Sciences, Faculty of Veterinary Medicine, Kasetsart University, Bangkok 10900, Thailand
| | - Sittiruk Roytrakul
- National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency, Pathum Thani 12120, Thailand
| | - Sekkarin Ploypetch
- Department of Clinical Sciences and Public Health, Faculty of Veterinary Science, Mahidol University, Nakhon Pathom 73170, Thailand
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Yakti W, Förster N, Müller M, Beck S, Schulz S, Mewis I, Ulrichs C. Solid-state fermentation of hemp waste: enhancing the performance of Hermetia illucens larvae and altering the composition of hemp secondary metabolites. Front Bioeng Biotechnol 2025; 13:1449233. [PMID: 39926358 PMCID: PMC11802502 DOI: 10.3389/fbioe.2025.1449233] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Accepted: 01/06/2025] [Indexed: 02/11/2025] Open
Abstract
Solid-state fermentation (SSF) can increase the nutritional quality of low value substrates for insects. In this study, SSF using different fungal species was applied on a hemp waste substrate, and the fermentation was followed by a black soldier fly larvae (BSFL) feeding experiment during which 300 larvae were grown on 200 g (20.1% DM) substrate for 7-9 days depending on the treatment. Besides assessing the BSFL performance parameters, the presence of hemp cannabinoids, flavonoids, and terpenes was assessed through the process and compared among the treatments. The results show that BSFL growth parameters varied depending on the fungal species used. Fermenting the substrate with Ganoderma lucidum can lead to an increase in the BSFL dry yield (4.54 g) compared to the untreated substrate (2.86 g), likely due to enhancing carbon accessibility in the substrate. SSF using Trichoderma reesei increased the cannabidiol and ∆9-tetrahydrocannabinol mass fractions in the substrate, and consequently in the produced BSFL biomass, while decreasing the amounts of acidic cannabinoids. Both Hypsizygus ulmarius and Pleurotus ostreatus effectively removed cannabinoids from the substrate. This study confirms that pre-treating hemp wastes via SSF can enhance their nutritional value and/or reduce bioactive secondary metabolites, with different fungal species offering different and complementary performances in achieving different biotechnological goals.
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Affiliation(s)
- Wael Yakti
- Faculty of Life Sciences, Thaer-Institute of Agricultural and Horticultural Sciences, Urban Plant Ecophysiology Division, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Nadja Förster
- Faculty of Life Sciences, Thaer-Institute of Agricultural and Horticultural Sciences, Urban Plant Ecophysiology Division, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Marcus Müller
- Faculty of Life Sciences, Thaer-Institute of Agricultural and Horticultural Sciences, Urban Plant Ecophysiology Division, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Sebastian Beck
- Department of Chemistry, Faculty of Mathematics and Natural Sciences, Applied Analytical and Environmental Chemistry, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Simon Schulz
- Faculty of Life Sciences, Thaer-Institute of Agricultural and Horticultural Sciences, Urban Plant Ecophysiology Division, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Inga Mewis
- Faculty of Life Sciences, Thaer-Institute of Agricultural and Horticultural Sciences, Urban Plant Ecophysiology Division, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Christian Ulrichs
- Faculty of Life Sciences, Thaer-Institute of Agricultural and Horticultural Sciences, Urban Plant Ecophysiology Division, Humboldt-Universität zu Berlin, Berlin, Germany
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5
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Liktor-Busa E, Largent-Milnes TM. Natural Products Derived from Cannabis sativa for Pain Management. Handb Exp Pharmacol 2025; 287:239-263. [PMID: 38509238 DOI: 10.1007/164_2024_710] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/22/2024]
Abstract
Cannabis sativa is one of the oldest medicinal plants in human history. Even ancient physicians from hundreds of years ago used Cannabis sativa to treat several conditions like pain. In the modern era, the research community, including health-care providers, have witnessed wide-scale changes in cannabis policy, legislation, and marketing, with a parallel increase in patient interest. A simple search in PubMed using "cannabis and pain" as keywords provides more than 2,400 articles, about 80% of which were published in the last 8-10 years. Several advancements have been achieved in understanding the complex chemistry of cannabis along with its multiple pharmacological activities. Preclinical data have demonstrated evidence for the promising potential of cannabis for pain management, and the continuous rise in the prevalence of pain increases the urgency to translate this into clinical practice. Despite the large body of cannabis literature, researchers still need to find rigorous answers for the questions about the efficacy and safety of cannabis in treatment of certain disorders such as pain. In the current chapter, we seek to present a critical overview about the current knowledge on cannabis with special emphasis on pain-related disorders.
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Weerts EM, Jenkins BW, Kuang RY, Hausker A, Moore CF. Orally administered Cannabigerol (CBG) in rats: Cannabimimetic actions, anxiety-like behavior, and inflammation-induced pain. Pharmacol Biochem Behav 2024; 245:173883. [PMID: 39322049 DOI: 10.1016/j.pbb.2024.173883] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 09/16/2024] [Accepted: 09/22/2024] [Indexed: 09/27/2024]
Abstract
Cannabigerol (CBG) is a phytocannabinoid found in cannabis that is promoted for medical use and other health benefits, but current empirical data on the behavioral effects of CBG are lacking. The purpose of this study was to evaluate the effects of a wide dose range of orally administered CBG on outcomes related to its potential cannabimimetic effects (cannabinoid tetrad), as well as effects on anxiety-like behavior, inflammation and related pain hypersensitivity. In a series of experiments, male and female Sprague Dawley rats received oral CBG (per os [p.o.]) or vehicle prior to testing of effects on 1) the cannabinoid tetrad (30-600 mg/kg, p.o.): assessments of locomotor activity, body temperature, antinociception (tail flick test), and catalepsy (bar test); 2) acoustic startle response (ASR) test of anxiety-like behavior (30-300 mg/kg, p.o.); 3) carrageenan-induced inflammation (paw edema), hyperalgesia (Hargreaves test), and allodynia (von Frey test) tests (10-60 mg/kg, p.o.). Positive control groups were administered THC (0-30 mg/kg, p.o.) for the cannabinoid tetrad assay, the benzodiazepine lorazepam (0-3 mg/kg, intraperitoneal [i.p.]) for the ASR test, or the opioid analgesic morphine (0-10 mg/kg, i.p.) for the carrageenan-induced inflammation and pain hypersensitivity tests. CBG did not produce cannabimimetic actions in the tetrad, but increased locomotor activity at the highest doses (300-600 mg/kg). THC produced typical dose-related cannabimimetic effects. CBG did not produce anxiolytic effects in the ASR test, while groups pretreated with lorazepam showed reductions in ASR. Finally, pretreatment with CBG prior to an intraplantar injection of carrageenan did not prevent the induction of an acute inflammatory state (i.e., increased paw edema and associated hyperalgesia and allodynia). In contrast, morphine alleviated hyperalgesia and allodynia induced by intraplantar carrageenan but did not affect the development of paw edema. In sum, these data do not support the use of oral CBG for anxiety or inflammatory pain.
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Affiliation(s)
- Elise M Weerts
- Division of Behavioral Biology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, USA
| | - Bryan W Jenkins
- Division of Behavioral Biology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, USA
| | - Robbie Y Kuang
- Division of Behavioral Biology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, USA
| | - Alma Hausker
- Division of Behavioral Biology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, USA
| | - Catherine F Moore
- Division of Behavioral Biology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, USA.
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7
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Nascimento GC, Escobar-Espinal D, Bálico GG, Silva NR, Del-Bel E. Cannabidiol and pain. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2024; 177:29-63. [PMID: 39029988 DOI: 10.1016/bs.irn.2024.04.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/21/2024]
Abstract
Chronic pain presents significant personal, psychological, and socioeconomic hurdles, impacting over 30% of adults worldwide and substantially contributing to disability. Unfortunately, current pharmacotherapy often proves inadequate, leaving fewer than 70% of patients with relief. This shortfall has sparked a drive to seek alternative treatments offering superior safety and efficacy profiles. Cannabinoid-based pharmaceuticals, notably cannabidiol (CBD), hold promise in pain management, driven by their natural origins, versatility, and reduced risk of addiction. As we navigate the opioid crisis, ongoing research plunges into CBD's therapeutic potential, buoyed by animal studies revealing its pain-relieving prowess through various system tweaks. However, the efficacy of cannabis in chronic pain management remains a contentious and stigmatized issue. The International Association for the Study of Pain (IASP) presently refrains from endorsing cannabinoid use for pain relief. Nevertheless, evidence indicates their potential in alleviating cancer-related, neuropathic, arthritis, and musculoskeletal pain, necessitating further investigation. Crucially, our comprehension of CBD's role in pain management is a journey still unfolding, with animal studies illustrating its analgesic effects through interactions with the endocannabinoid, inflammatory, and nociceptive systems. As the plot thickens, it's clear: the saga of chronic pain and CBD's potential offers a compelling narrative ripe for further exploration and understanding.
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Affiliation(s)
- Glauce Crivelaro Nascimento
- Department of Basic and Oral Biology, School of Dentistry of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, SP, Brazil.
| | - Daniela Escobar-Espinal
- Department of Basic and Oral Biology, School of Dentistry of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, SP, Brazil
| | - Gabriela Gonçalves Bálico
- Department of Basic and Oral Biology, School of Dentistry of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, SP, Brazil
| | | | - Elaine Del-Bel
- Department of Basic and Oral Biology, School of Dentistry of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, SP, Brazil; National Institute for Science and Technology, Translational Medicine, University of Sao Paulo, Ribeirao Preto, SP, Brazil; Center for Cannabinoid Research, Mental Health Building, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, SP, Brazil
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8
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Botea MO, Andereggen L, Urman RD, Luedi MM, Romero CS. Cannabinoids for Acute Pain Management: Approaches and Rationale. Curr Pain Headache Rep 2024; 28:681-689. [PMID: 38607548 PMCID: PMC11271357 DOI: 10.1007/s11916-024-01252-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/28/2024] [Indexed: 04/13/2024]
Abstract
PURPOSE OF THE REVIEW Acute pain management remains a challenge and postoperative pain is often undermanaged despite many available treatment options, also including cannabinoids. RECENT FINDINGS In the light of the opioid epidemic, there has been growing interest in alternative care bundles for pain management, including cannabinoids as potential treatment to decrease opioid prescribing. Despite the lack of solid evidence on the efficacy of cannabinoids, their use among patients with pain, including those using opioids, is currently increasing. This use is supported by data suggesting that cannabinoids could potentially contribute to a better pain management and to a reduction in opioid doses while maintaining effective analgesia with minimum side effects. The scientific basis for supporting the use of cannabis is extensive, although it does not necessarily translate into relevant clinical outcomes. The use of cannabinoids in acute pain did not always consistently show statistically significant results in improving acute pain. Large randomized, controlled trials evaluating diverse cannabis extracts are needed in different clinical pain populations to determine safety and efficacy.
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Affiliation(s)
- Mihai O Botea
- Department of Anaesthesiology and Critical Care, Medicover Pelican Clinic Hospital, Oradea, Romania
| | - Lukas Andereggen
- Department of Neurosurgery, Cantonal Hospital of Aarau, Aarau, Switzerland
- Faculty of Medicine, University of Bern, Bern, Switzerland
| | - Richard D Urman
- Department of Anaesthesiology, The Ohio State University, Columbus, OH, 43210, USA
| | - Markus M Luedi
- Department of Anaesthesiology, Rescue- and Pain Medicine, Cantonal Hospital of St, Gallen, St. Gallen, Switzerland.
- Department of Anaesthesiology and Pain Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
| | - Carolina S Romero
- Department of Anaesthesiology and Critical Care, Hospital General Universitario De Valencia, Valencia, Spain
- Research Methods Department, Universidad Europea de Valencia, Valencia, Spain
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Zhu K, Chen S, Qin X, Bai W, Hao J, Xu X, Guo H, Bai H, Yang Z, Wang S, Zhao Z, Ji T, Kong D, Zhang W. Exploring the therapeutic potential of cannabidiol for sleep deprivation-induced hyperalgesia. Neuropharmacology 2024; 249:109893. [PMID: 38428482 DOI: 10.1016/j.neuropharm.2024.109893] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 02/21/2024] [Accepted: 02/26/2024] [Indexed: 03/03/2024]
Abstract
Hyperalgesia resulting from sleep deprivation (SD) poses a significant a global public health challenge with limited treatment options. The nucleus accumbens (NAc) plays a crucial role in the modulation of pain and sleep, with its activity regulated by two distinct types of medium spiny neurons (MSNs) expressing dopamine 1 or dopamine 2 (D1-or D2) receptors (referred to as D1-MSNs and D2-MSNs, respectively). However, the specific involvement of the NAc in SD-induced hyperalgesia remains uncertain. Cannabidiol (CBD), a nonpsychoactive phytocannabinoid, has demonstrated analgesic effects in clinical and preclinical studies. Nevertheless, its potency in addressing this particular issue remains to be determined. Here, we report that SD induced a pronounced pronociceptive effect attributed to the heightened intrinsic excitability of D2-MSNs within the NAc in Male C57BL/6N mice. CBD (30 mg/kg, i.p.) exhibited an anti-hyperalgesic effect. CBD significantly improved the thresholds for thermal and mechanical pain and increased wakefulness by reducing delta power. Additionally, CBD inhibited the intrinsic excitability of D2-MSNs both in vitro and in vivo. Bilateral microinjection of the selective D2 receptor antagonist raclopride into the NAc partially reversed the antinociceptive effect of CBD. Thus, these findings strongly suggested that SD activates NAc D2-MSNs, contributing heightened to pain sensitivity. CBD exhibits antinociceptive effects by activating D2R, thereby inhibiting the excitability of D2-MSNs and promoting wakefulness under SD conditions.
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Affiliation(s)
- Kangsheng Zhu
- Department of Pharmacology of Chinese Materia Medica, Institution of Chinese Integrative Medicine, School of Chinese Integrative Medicine, The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Shijiazhuang, Hebei, 050017, China; Department of Anesthesiology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050011, China
| | - Siruan Chen
- Department of Pharmacology of Chinese Materia Medica, Institution of Chinese Integrative Medicine, School of Chinese Integrative Medicine, The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Shijiazhuang, Hebei, 050017, China
| | - Xia Qin
- Department of Pharmacology of Chinese Materia Medica, Institution of Chinese Integrative Medicine, School of Chinese Integrative Medicine, The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Shijiazhuang, Hebei, 050017, China
| | - Wanjun Bai
- Department of Pharmacy, Hebei General Hospital, Shijiazhuang, Hebei, 050051, China
| | - Jie Hao
- Department of Pharmacology of Chinese Materia Medica, Institution of Chinese Integrative Medicine, School of Chinese Integrative Medicine, The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Shijiazhuang, Hebei, 050017, China
| | - Xiaolei Xu
- School of Nursing, Hebei Medical University, Shijiazhuang, Hebei, 050000, China
| | - Han Guo
- Department of Pharmacology of Chinese Materia Medica, Institution of Chinese Integrative Medicine, School of Chinese Integrative Medicine, The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Shijiazhuang, Hebei, 050017, China
| | - Hui Bai
- Department of Cardiac Ultrasound, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050017, China
| | - Zuxiao Yang
- Department of Pharmacology of Chinese Materia Medica, Institution of Chinese Integrative Medicine, School of Chinese Integrative Medicine, The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Shijiazhuang, Hebei, 050017, China
| | - Sheng Wang
- Hebei Key Laboratory of Neurophysiology, Shijiazhuang, Hebei, 050017, China
| | - Zongmao Zhao
- Department of Neurosurgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050011, China
| | - Tengfei Ji
- Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China
| | - Dezhi Kong
- Department of Pharmacology of Chinese Materia Medica, Institution of Chinese Integrative Medicine, School of Chinese Integrative Medicine, The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Shijiazhuang, Hebei, 050017, China.
| | - Wei Zhang
- Department of Pharmacology of Chinese Materia Medica, Institution of Chinese Integrative Medicine, School of Chinese Integrative Medicine, The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Hebei Medical University, Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Shijiazhuang, Hebei, 050017, China.
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10
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Thomson ACS, McCarrel TM, Zakharov A, Gomez B, Lyubimov A, Schwark WS, Mallicote MF, Portela DA, Bisiau AL, Wakshlag JJ. Pharmacokinetics and tolerability of single-dose enteral cannabidiol and cannabidiolic acid rich hemp in horses ( Equus caballus). Front Vet Sci 2024; 11:1356463. [PMID: 38681854 PMCID: PMC11047043 DOI: 10.3389/fvets.2024.1356463] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Accepted: 03/26/2024] [Indexed: 05/01/2024] Open
Abstract
The pharmacokinetics and tolerability of cannabinoids and their metabolites were determined in eight horses after enteral administration of a commercial CBD/CBDA-rich hemp oil product. Each horse was administered 2 mg/kg or 8 mg/kg CBD/CBDA or no treatment in a randomized cross-over design. Serial serum samples collected over 48 h were analyzed by high performance liquid chromatography with tandem mass spectrometry. Plasma chemistry analysis was performed at 0 h and 24 h. Vital parameters, pedometry, and blinded mentation and gait evaluations were recorded at intervals up to 24 h. Manure production and gastrointestinal transit time were tracked for 48 h after oil administration. The median maximal concentration of CBD and CBDA were 5.2 and 36.95 ng/mL in the 2 mg/kg group, respectively; and 40.35 and 353.56 ng/mL in the 8 mg/kg group. The median half-life of elimination was not calculated for the 2 mg/kg CBD treatment due to lack of time points above the lower quantifiable limit beyond the Cmax while it was 7.75 h in the 8 mg/kg group. CBDA absorption was biphasic. Pharmacokinetic parameters for tetrahydrocannabinol, tetrahydrocannabinolic acid, cannabigerolic acid, and 7-carboxy cannabidiol are also reported. No significant differences in any of the measured tolerability parameters were demonstrated between treatment groups. Single-dose enteral administration of CBD/CBDA-rich hemp extract up to 8 mg/kg does not appear to produce neurologic, behavioral, or gastrointestinal effects in horses.
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Affiliation(s)
- Alexander C. S. Thomson
- Department of Comparative, Population, and Diagnostic Medicine, College of Veterinary Medicine, University of Florida, Gainesville, FL, United States
| | - Taralyn M. McCarrel
- Department of Large Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL, United States
| | - Alexander Zakharov
- Department of Pharmacology, College of Medicine, University of Illinois, Chicago, IL, United States
| | - Beatriz Gomez
- Department of Pharmacology, College of Medicine, University of Illinois, Chicago, IL, United States
| | - Alex Lyubimov
- Department of Pharmacology, College of Medicine, University of Illinois, Chicago, IL, United States
| | - Wayne S. Schwark
- Department of Molecular Medicine, College of Veterinary Medicine, Cornell University, Ithaca, NY, United States
| | - Martha F. Mallicote
- Department of Large Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL, United States
| | - Diego A. Portela
- Department of Comparative, Population, and Diagnostic Medicine, College of Veterinary Medicine, University of Florida, Gainesville, FL, United States
| | - Amber L. Bisiau
- Department of Large Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL, United States
| | - Joseph J. Wakshlag
- Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, United States
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11
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Arantes ALF, Carvalho MC, Brandão ML, Prado WA, Crippa JADS, Lovick TA, Genaro K. Antinociceptive action of cannabidiol on thermal sensitivity and post-operative pain in male and female rats. Behav Brain Res 2024; 459:114793. [PMID: 38048909 DOI: 10.1016/j.bbr.2023.114793] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Revised: 11/22/2023] [Accepted: 11/30/2023] [Indexed: 12/06/2023]
Abstract
This study investigated the antinociceptive potential of cannabidiol (CBD) in male and female Wistar rats. The assessment and analysis included tail withdrawal to thermal stimulation (tail flick test) and mechanical allodynia induced by plantar incision injury (von Frey test). CBD reduced acute thermal sensitivity in uninjured animals and post-operative mechanical allodynia in males and females. In the tail flick test, CBD 30 mg/kg i.p. was required to induce antinociception in males. During the proestrus phase, females did not show a statistically significant antinociceptive response to CBD treatment despite a noticeable trend. In contrast, in a separate group of rats tested during the late diestrus phase, antinociception varied with CBD dosage and time. In the post-operative pain model, CBD at 3 mg/kg decreased mechanical allodynia in males. Similarly, this dose reduced allodynia in females during proestrus. However, in females during late diestrus, the lower dose of CBD (0.3 mg/kg) reduced mechanical allodynia, although the latency to onset of the effect was slower (90 min). The effectiveness of a 10-fold lower dose of CBD during the late diestrus stage in females suggests that ovarian hormones can influence the action of CBD. While CBD has potential for alleviating pain in humans, personalized dosing regimens may need to be developed to treat pain in women.
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Affiliation(s)
- Ana Luisa Ferreira Arantes
- Institute of Neurosciences and Behavior and Laboratory of Neuropsychopharmacology of Faculty of Philosophy, Sciences and Letters of University of São Paulo, Ribeirao Preto, SP 14040-900, Brazil
| | - Milene Cristina Carvalho
- Department of Neuroscience and Behavioral Sciences, Ribeirão Preto Medical School, University of São Paulo, SP 14040-900, Brazil; Institute of Neurosciences and Behavior and Laboratory of Neuropsychopharmacology of Faculty of Philosophy, Sciences and Letters of University of São Paulo, Ribeirao Preto, SP 14040-900, Brazil
| | - Marcus Lira Brandão
- Institute of Neurosciences and Behavior and Laboratory of Neuropsychopharmacology of Faculty of Philosophy, Sciences and Letters of University of São Paulo, Ribeirao Preto, SP 14040-900, Brazil
| | - Wiliam Alves Prado
- Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, SP 14040-900, Brazil
| | - José Alexandre de Souza Crippa
- Department of Neuroscience and Behavioral Sciences, Ribeirão Preto Medical School, University of São Paulo, SP 14040-900, Brazil; National Institute of Science and Technology for Translational Medicine, Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (INCT-TM, CNPq), Brasília, DF 71605-001, Brazil
| | - Thelma Anderson Lovick
- Physiology, Pharmacology & Neuroscience, University of Bristol, Bristol BS8 1TD, United Kingdom
| | - Karina Genaro
- Department of Anesthesiology, School of Medicine, University of California, Irvine, CA 92617, USA.
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12
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Kim JH, Hong M, Han JH, Ryu BR, Lim YS, Lim JD, Kim CH, Lee SU, Kwon TH. In Vitro and In Vivo Anti-Inflammatory Effects of Cannabidiol Isolated from Novel Hemp ( Cannabis sativa L.) Cultivar Pink Pepper. Molecules 2023; 28:6439. [PMID: 37764215 PMCID: PMC10535604 DOI: 10.3390/molecules28186439] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Revised: 08/31/2023] [Accepted: 09/03/2023] [Indexed: 09/29/2023] Open
Abstract
Cannabis sativa L. contains more than 80 cannabinoids, among which cannabidiol (CBD) is the main neuroactive component. We aimed to investigate the anti-inflammatory efficacy of CBD in vitro and in vivo isolated from "Pink pepper", a novel hemp cultivar, by repeating the method of selecting and cultivating individuals with the highest CBD content. We investigated the effects of CBD on inflammatory markers elevated by lipopolysaccharide (LPS) treatment in RAW 264.7 mouse macrophage cells through Western blot and RT-PCR. In addition, we confirmed these effects through the ELISA of inflamed paw tissue of a λ-carrageenan-induced mouse edema model that received an oral administration of CBD. CBD inhibited the LPS-induced phosphorylation of NF-κB and MAPK in RAW 264.7 and exhibited anti-inflammatory effects by participating in these pathways. In our in vivo study, we confirmed that CBD also inhibited the inflammatory mediators of proteins extracted from edematous mouse paw tissue. These results show that CBD isolated from "Pink pepper" exhibits potent anti-inflammatory effects. These anti-inflammatory effects of CBD have pharmacological and physiological significance, highlighting the industrial value of this novel cultivar.
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Affiliation(s)
- Jong-Hui Kim
- Institute of Biological Resources, Chuncheon Bioindustry Foundation, Chuncheon 24232, Republic of Korea; (J.-H.K.); (M.H.); (J.-H.H.); (C.H.K.)
| | - Min Hong
- Institute of Biological Resources, Chuncheon Bioindustry Foundation, Chuncheon 24232, Republic of Korea; (J.-H.K.); (M.H.); (J.-H.H.); (C.H.K.)
| | - Joon-Hee Han
- Institute of Biological Resources, Chuncheon Bioindustry Foundation, Chuncheon 24232, Republic of Korea; (J.-H.K.); (M.H.); (J.-H.H.); (C.H.K.)
| | - Byeong Ryeol Ryu
- Department of Bio-Health Convergence, Graduate School, Kangwon National University, Chuncheon 24341, Republic of Korea; (B.R.R.); (Y.S.L.); (J.D.L.)
| | - Young Seok Lim
- Department of Bio-Health Convergence, Graduate School, Kangwon National University, Chuncheon 24341, Republic of Korea; (B.R.R.); (Y.S.L.); (J.D.L.)
- Department of Bio-Health Technology, Kangwon National University, Chuncheon 24341, Republic of Korea
| | - Jung Dae Lim
- Department of Bio-Health Convergence, Graduate School, Kangwon National University, Chuncheon 24341, Republic of Korea; (B.R.R.); (Y.S.L.); (J.D.L.)
- Department of Herbal Medicine Resource, Kangwon National University, Samcheok 25949, Republic of Korea
| | - Chang Hyeug Kim
- Institute of Biological Resources, Chuncheon Bioindustry Foundation, Chuncheon 24232, Republic of Korea; (J.-H.K.); (M.H.); (J.-H.H.); (C.H.K.)
| | - Soo-Ung Lee
- Institute of Biological Resources, Chuncheon Bioindustry Foundation, Chuncheon 24232, Republic of Korea; (J.-H.K.); (M.H.); (J.-H.H.); (C.H.K.)
| | - Tae-Hyung Kwon
- Institute of Biological Resources, Chuncheon Bioindustry Foundation, Chuncheon 24232, Republic of Korea; (J.-H.K.); (M.H.); (J.-H.H.); (C.H.K.)
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13
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Christensen C, Rose M, Cornett C, Allesø M. Decoding the Postulated Entourage Effect of Medicinal Cannabis: What It Is and What It Isn't. Biomedicines 2023; 11:2323. [PMID: 37626819 PMCID: PMC10452568 DOI: 10.3390/biomedicines11082323] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 08/11/2023] [Accepted: 08/16/2023] [Indexed: 08/27/2023] Open
Abstract
The 'entourage effect' term was originally coined in a pre-clinical study observing endogenous bio-inactive metabolites potentiating the activity of a bioactive endocannabinoid. As a hypothetical afterthought, this was proposed to hold general relevance to the usage of products based on Cannabis sativa L. The term was later juxtaposed to polypharmacy pertaining to full-spectrum medicinal Cannabis products exerting an overall higher effect than the single compounds. Since the emergence of the term, a discussion of its pharmacological foundation and relevance has been ongoing. Advocates suggest that the 'entourage effect' is the reason many patients experience an overall better effect from full-spectrum products. Critics state that the term is unfounded and used primarily for marketing purposes in the Cannabis industry. This scoping review aims to segregate the primary research claiming as well as disputing the existence of the 'entourage effect' from a pharmacological perspective. The literature on this topic is in its infancy. Existing pre-clinical and clinical studies are in general based on simplistic methodologies and show contradictory findings, with the clinical data mostly relying on anecdotal and real-world evidence. We propose that the 'entourage effect' is explained by traditional pharmacological terms pertaining to other plant-based medicinal products and polypharmacy in general (e.g., synergistic interactions and bioenhancement).
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Affiliation(s)
- Catalina Christensen
- Tetra Pharm Technologies ApS, Rugmarken 10, DK-3650 Ølstykke, Denmark; (M.R.); (M.A.)
| | - Martin Rose
- Tetra Pharm Technologies ApS, Rugmarken 10, DK-3650 Ølstykke, Denmark; (M.R.); (M.A.)
| | - Claus Cornett
- Department of Pharmacy, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark;
| | - Morten Allesø
- Tetra Pharm Technologies ApS, Rugmarken 10, DK-3650 Ølstykke, Denmark; (M.R.); (M.A.)
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14
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Bekkouch O, Zengin G, Harnafi M, Touiss I, Khoulati A, Saalaoui E, Harnafi H, Abdellattif MH, Amrani S. Anti-Inflammatory Study and Phytochemical Characterization of Zingiber officinale Roscoe and Citrus limon L. Juices and Their Formulation. ACS OMEGA 2023; 8:26715-26724. [PMID: 37546676 PMCID: PMC10398691 DOI: 10.1021/acsomega.2c04263] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Accepted: 01/09/2023] [Indexed: 08/08/2023]
Abstract
Zingiber officinale and Citrus limon, well known as ginger and lemon, are two vegetals widely used in traditional medicine and the culinary field. The juices of the two vegetals were evaluated based on their inflammation, both in vivo and in vitro. High-performance liquid chromatography (HPLC) was used to characterize different juices from Zingiber officinale Roscoe and Citrus limon. After the application of the HPLC method, different compounds were identified, such as 6-gingerol and 6-gingediol from the ginger juice and isorhamnetin and hesperidin from the lemon juice. In addition, the two juices and their formulation were assessed for their anti-inflammatory activity, in vitro by utilizing the BSA denaturation test, in vivo using the carrageenan-induced inflammation test, and the vascular permeability test. Important and statistically significant anti-inflammatory activities were observed for all juices, especially the formulation. The results of our work showed clearly that the Zingiber officinale and Citrus limon juices protect in vivo the development of the rat paw edema, especially the formulation F composed of the Zingiber officinale and Citrus limon juices, which shows an anti-inflammatory activity equal to -35.95% and -44.05% using 10 and 20 mg/kg of the dose, respectively. Our work also showed that the formulation was the most effective tested extract since it inhibits the vascular permeability by -37% and -44% at the doses of 200 and 400 mg/kg, respectively, and in vitro via the inhibition of the denaturation of BSA by giving a synergetic effect with the highest IC50 equal to 684.61 ± 7.62 μg/mL corresponding to the formulation F. This work aims to develop nutraceutical preparations in the future and furnishes the support for a new investigation into the activities of the various compounds found in Zingiber officinale Roscoe and Citrus limon.
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Affiliation(s)
- Oussama Bekkouch
- Laboratory
of Bioresources, Biotechnology, Ethnopharmacology and Health, Faculty
of Sciences, Mohammed First University, Oujda60000, Morocco
| | - Gökhan Zengin
- Physiology
and Biochemistry Research Laboratory, Department of Biology, Science
Faculty, Selcuk University, 42130Konya, Turkey
| | - Mohamed Harnafi
- Laboratory
of Bioresources, Biotechnology, Ethnopharmacology and Health, Faculty
of Sciences, Mohammed First University, Oujda60000, Morocco
| | - Ilham Touiss
- Laboratory
of Bioresources, Biotechnology, Ethnopharmacology and Health, Faculty
of Sciences, Mohammed First University, Oujda60000, Morocco
| | - Amine Khoulati
- Laboratory
of Bioresources, Biotechnology, Ethnopharmacology and Health, Faculty
of Sciences, Mohammed First University, Oujda60000, Morocco
| | - Ennouamane Saalaoui
- Laboratory
of Bioresources, Biotechnology, Ethnopharmacology and Health, Faculty
of Sciences, Mohammed First University, Oujda60000, Morocco
| | - Hicham Harnafi
- Laboratory
of Bioresources, Biotechnology, Ethnopharmacology and Health, Faculty
of Sciences, Mohammed First University, Oujda60000, Morocco
| | - Magda H. Abdellattif
- Chemistry
Department, Sciences College, Taif University, P.O. Box 11099, Taif21944, Saudi Arabia
| | - Souliman Amrani
- Laboratory
of Bioresources, Biotechnology, Ethnopharmacology and Health, Faculty
of Sciences, Mohammed First University, Oujda60000, Morocco
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15
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Schlemper V, Dal Molin CB, Frankenberger L, Biavatti MW, de Mello Schlemper SR. Inhibitory effect of hydroalcoholic extract of Cunila spicata Benth. on phlogistic agents-induced cellular migration in the airways of mice. JOURNAL OF ETHNOPHARMACOLOGY 2023; 311:116477. [PMID: 37031822 DOI: 10.1016/j.jep.2023.116477] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 04/03/2023] [Accepted: 04/07/2023] [Indexed: 06/19/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Cunila spicata Benth. Is a creeping and aromatic plant that has an ethnopharmacological indication in the southern region of Brazil, in the Araucaria Forest biome. It's used as an alternative therapy for respiratory diseases for men and animals since the "tropeirista" movement in colonial Brazil. AIM OF THE STUDY Investigate the influence of oral administration of hydroalcoholic extract of C. spicata (HECS) on cellular inflammatory processes in the airways of mice. MATERIAL AND METHODS The HECS was obtained by the ultrasound-assisted technique. Phytochemical analysis of the volatile compounds was performed using gas-chromatography with mass spectrometry. To investigate the biological activity of HECS, the animals were pre-treated with HECS orally 1 h before and the bronchoalveolar lavage (BAL) model was used, in which the animals were subjected to inhalation of different pro-inflammatory agents such as carrageenan (CAR), histamine (HIST), capsaicin (CAP), bradykinin (BK), and 48/80 compound (C48/80). After sacrifice, BAL sample was collected from the bronchi and was analyzed for total and differential white blood cell counts, compared with control groups. RESULTS Fourteen volatile phytocompounds were identified in the HECS, the main ones being 2-bornanone, menthofuran and camphene. Among the HECS treated animals, all showed significant maximal inhibition (MI) when challenged with pro-inflammatory agents by nebulization. In the group of animals that received CAR, the MI was 72.77 ± 3.88%, compared to the negative control (NC). There was a predominance of lymphocytes (59.18 ± 4.07%). For the HIST group, MI was 64.03 ± 4.33%, in relation to the NC, with predominance in macrophages number (76.53 ± 2.78%). In the CAP group, the MI obtained was 38.90 ± 11.31%, with greater macrophage migration occurring (80.98 ± 3.44%) in the higher dose. For animals subjected to BK inhalation, the MI was 48.63 ± 3.95% with macrophages predominance (64.33 ± 10.04%). In the group that received C48/80 inhalation, the MI was 40.25 ± 5.30% (100 mg kg-1), with higher occurrence of macrophages (72.97 ± 4.23%). CONCLUSION Our results suggest that HECS had a non-specific inhibitory effect on cellular migration induced by different pro-inflammatory agents, reducing inflammation in airways of mice. These effects coincide and support its ethnopharmacological use as an alternative medicine for respiratory diseases in regions where the plant is prevalent.
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Affiliation(s)
- Valfredo Schlemper
- School of Veterinary Medicine, Federal University of Fronteira Sul (UFFS), Campus Realeza, PR, Brazil; Post-graduation Program in Health, Welfare and Sustainable Animal Production in the Southern Border, Federal University of Fronteira Sul (UFFS), Realeza, PR, Brazil.
| | - Caroline Baldessar Dal Molin
- School of Veterinary Medicine, Federal University of Fronteira Sul (UFFS), Campus Realeza, PR, Brazil; Post-graduation Program in Health, Welfare and Sustainable Animal Production in the Southern Border, Federal University of Fronteira Sul (UFFS), Realeza, PR, Brazil
| | - Larissa Frankenberger
- Laboratory of Pharmacognosy, Department of Pharmaceutical Sciences, Federal University of Santa Catarina (UFSC), Florianópolis, SC, Brazil
| | - Maique Weber Biavatti
- Laboratory of Pharmacognosy, Department of Pharmaceutical Sciences, Federal University of Santa Catarina (UFSC), Florianópolis, SC, Brazil
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16
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Fiore M, Alfieri A, Di Franco S, Petrou S, Damiani G, Pace MC. Medicinal cannabis products for the treatment of acute pain. World J Clin Cases 2023; 11:2670-2676. [PMID: 37214578 PMCID: PMC10198104 DOI: 10.12998/wjcc.v11.i12.2670] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Revised: 03/10/2023] [Accepted: 03/27/2023] [Indexed: 04/25/2023] Open
Abstract
For thousands of years, medicinal cannabis has been used for pain treatment, but its use for pain management is still controversial. Meta-analysis of the literature has shown contrasting results on the addition of cannabinoids to opioids compared with placebo/other active agents to reduce pain. Clinical studies are mainly focused on medicinal cannabis use in chronic pain management, for which the analgesic effect has been proven in many studies. This review focuses on the potential use of medical cannabis for acute pain management in preclinical studies, studies on healthy subjects and the few pioneering studies in the clinical setting.
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Affiliation(s)
- Marco Fiore
- Department of Women, Child and General and Specialized Surgery, University of Campania “Luigi Vanvitelli”, Naples 80138, Italy
| | - Aniello Alfieri
- Department of Women, Child and General and Specialized Surgery, University of Campania “Luigi Vanvitelli”, Naples 80138, Italy
| | - Sveva Di Franco
- Department of Women, Child and General and Specialized Surgery, University of Campania “Luigi Vanvitelli”, Naples 80138, Italy
| | - Stephen Petrou
- Department of Emergency Medicine, University of California San Francisco, San Francisco, CA 94143, United States
| | - Giovanni Damiani
- Department of Biomedical, Surgical, and Dental Sciences, University of Milan, Milan 20122, Italy
| | - Maria Caterina Pace
- Department of Women, Child and General and Specialized Surgery, University of Campania “Luigi Vanvitelli”, Naples 80138, Italy
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17
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Kim J, Choi P, Park YT, Kim T, Ham J, Kim JC. The Cannabinoids, CBDA and THCA, Rescue Memory Deficits and Reduce Amyloid-Beta and Tau Pathology in an Alzheimer’s Disease-like Mouse Model. Int J Mol Sci 2023; 24:ijms24076827. [PMID: 37047798 PMCID: PMC10095267 DOI: 10.3390/ijms24076827] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 04/01/2023] [Accepted: 04/02/2023] [Indexed: 04/08/2023] Open
Abstract
Most studies related to hemp are focused on Cannabidiol (CBD) and Tetrahydrocannabinol (THC); however, up to 120 types of phytocannabinoids are present in hemp. Hemp leaves contain large amounts of Cannabidiolic acid (CBDA) and Tetrahydrocannabinolic acid (THCA), which are acidic variants of CBD and THC and account for the largest proportion of CBDA. In recent studies, CBDA exhibited anti-hyperalgesia and anti-inflammatory effects. THCA also showed anti-inflammatory and neuroprotective effects that may be beneficial for treating neurodegenerative diseases. CBDA and THCA can penetrate the blood–brain barrier (BBB) and affect the central nervous system. The purpose of this study was to determine whether CBDA and THCA ameliorate Alzheimer’s disease (AD)-like features in vitro and in vivo. The effect of CBDA and THCA was evaluated in the Aβ1–42-treated mouse model. We observed that Aβ1–42-treated mice had more hippocampal Aβ and p-tau levels, pathological markers of AD, and loss of cognitive function compared with PBS-treated mice. However, CBDA- and THCA-treated mice showed decreased hippocampal Aβ and p-tau and superior cognitive function compared with Aβ1–42-treated mice. In addition, CBDA and THCA lowered Aβ and p-tau levels, alleviated calcium dyshomeostasis, and exhibited neuroprotective effects in primary neurons. Our results suggest that CBDA and THCA have anti-AD effects and mitigate memory loss and resilience to increased hippocampal Ca2+, Aβ, and p-tau levels. Together, CBDA and THCA may be useful therapeutic agents for treating AD.
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Affiliation(s)
- Juyong Kim
- Department of Agricultural Biotechnology, Seoul National University, Seoul 08826, Republic of Korea
- Natural Product Research Center, Korea Institute of Science and Technology (KIST), Gangneung 25451, Republic of Korea
| | - Pilju Choi
- Natural Product Research Center, Korea Institute of Science and Technology (KIST), Gangneung 25451, Republic of Korea
| | - Young-Tae Park
- Natural Product Research Center, Korea Institute of Science and Technology (KIST), Gangneung 25451, Republic of Korea
| | - Taejung Kim
- Natural Product Research Center, Korea Institute of Science and Technology (KIST), Gangneung 25451, Republic of Korea
- Division of Bio-Medical Science & Technology, KIST School, University of Science and Technology, Seoul 02792, Republic of Korea
| | - Jungyeob Ham
- Natural Product Research Center, Korea Institute of Science and Technology (KIST), Gangneung 25451, Republic of Korea
- Division of Bio-Medical Science & Technology, KIST School, University of Science and Technology, Seoul 02792, Republic of Korea
- NeoCannBio Co., Ltd., Gangneung 02792, Republic of Korea
| | - Jin-Chul Kim
- Natural Product Research Center, Korea Institute of Science and Technology (KIST), Gangneung 25451, Republic of Korea
- Division of Bio-Medical Science & Technology, KIST School, University of Science and Technology, Seoul 02792, Republic of Korea
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18
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Dumbraveanu C, Strommer K, Wonnemann M, Choconta JL, Neumann A, Kress M, Kalpachidou T, Kummer KK. Pharmacokinetics of Orally Applied Cannabinoids and Medical Marijuana Extracts in Mouse Nervous Tissue and Plasma: Relevance for Pain Treatment. Pharmaceutics 2023; 15:853. [PMID: 36986714 PMCID: PMC10057980 DOI: 10.3390/pharmaceutics15030853] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 02/20/2023] [Accepted: 02/24/2023] [Indexed: 03/08/2023] Open
Abstract
Cannabis sativa plants contain a multitude of bioactive substances, which show broad variability between different plant strains. Of the more than a hundred naturally occurring phytocannabinoids, Δ9-Tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) have been the most extensively studied, but whether and how the lesser investigated compounds in plant extracts affect bioavailability or biological effects of Δ9-THC or CBD is not known. We therefore performed a first pilot study to assess THC concentrations in plasma, spinal cord and brain after oral administration of THC compared to medical marijuana extracts rich in THC or depleted of THC. Δ9-THC levels were higher in mice receiving the THC-rich extract. Surprisingly, only orally applied CBD but not THC alleviated mechanical hypersensitivity in the mouse spared nerve injury model, favoring CBD as an analgesic compound for which fewer unwanted psychoactive effects are to be expected.
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Affiliation(s)
- Cristiana Dumbraveanu
- Institute of Physiology, Medical University of Innsbruck, 6020 Innsbruck, Austria
- Bionorica Research GmbH, 6020 Innsbruck, Austria
| | | | | | - Jeiny Luna Choconta
- Institute of Physiology, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | | | - Michaela Kress
- Institute of Physiology, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | - Theodora Kalpachidou
- Institute of Physiology, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | - Kai K. Kummer
- Institute of Physiology, Medical University of Innsbruck, 6020 Innsbruck, Austria
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19
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Hasbi A, Madras BK, George SR. Endocannabinoid System and Exogenous Cannabinoids in Depression and Anxiety: A Review. Brain Sci 2023; 13:brainsci13020325. [PMID: 36831868 PMCID: PMC9953886 DOI: 10.3390/brainsci13020325] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Revised: 02/10/2023] [Accepted: 02/11/2023] [Indexed: 02/17/2023] Open
Abstract
Background: There is a growing liberalization of cannabis-based preparations for medical and recreational use. In multiple instances, anxiety and depression are cited as either a primary or a secondary reason for the use of cannabinoids. Aim: The purpose of this review is to explore the association between depression or anxiety and the dysregulation of the endogenous endocannabinoid system (ECS), as well as the use of phytocannabinoids and synthetic cannabinoids in the remediation of depression/anxiety symptoms. After a brief description of the constituents of cannabis, cannabinoid receptors and the endocannabinoid system, the most important evidence is presented for the involvement of cannabinoids in depression and anxiety both in human and from animal models of depression and anxiety. Finally, evidence is presented for the clinical use of cannabinoids to treat depression and anxiety. Conclusions: Although the common belief that cannabinoids, including cannabis, its main studied components-tetrahydrocannabinol (THC) and cannabidiol (CBD)-or other synthetic derivatives have been suggested to have a therapeutic role for certain mental health conditions, all recent systematic reviews that we report have concluded that the evidence that cannabinoids improve depressive and anxiety disorders is weak, of very-low-quality, and offers no guidance on the use of cannabinoids for mental health conditions within a regulatory framework. There is an urgent need for high-quality studies examining the effects of cannabinoids on mental disorders in general and depression/anxiety in particular, as well as the consequences of long-term use of these preparations due to possible risks such as addiction and even reversal of improvement.
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Affiliation(s)
- Ahmed Hasbi
- Department of Pharmacology and Toxicology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada
- Correspondence: (A.H.); (S.R.G.)
| | - Bertha K. Madras
- McLean Hospital, Belmont, MA 02478, USA
- Department of Psychiatry, Harvard Medical School, Boston, MA 02115, USA
| | - Susan R. George
- Department of Pharmacology and Toxicology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada
- Department of Medicine, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada
- Correspondence: (A.H.); (S.R.G.)
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Yakti W, Förster N, Müller M, Mewis I, Ulrichs C. Hemp Waste as a Substrate for Hermetia illucens (L.) (Diptera: Stratiomyidae) and Tenebrio molitor L. (Coleoptera: Tenebrionidae) Rearing. INSECTS 2023; 14:183. [PMID: 36835752 PMCID: PMC9960234 DOI: 10.3390/insects14020183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 02/08/2023] [Accepted: 02/10/2023] [Indexed: 06/18/2023]
Abstract
The proper treatment of cannabis agricultural wastes can reduce the environmental impact of its cultivation and generate valuable products. This study aimed to test the potential of cannabis agricultural wastes as a substrate for the rearing of black soldier fly larvae (BSFL) and yellow mealworms (MW). In the case of BSFL, replacing the fibre component (straw) in the substrate with the hemp waste can increase the nutritional value of the substrate and led to bigger larvae. The bigger larvae had lower P and Mg, and higher Fe and Ca. Crude protein also varied based on the size of larvae and/or the content of protein in the initial substrate, which was boosted by replacing straw with hemp material. No other cannabinoids than cannabidiolic acid (CBDA), cannabigerolic acid (CBGA), and cannabidiol (CBD) were found in significant amounts in the larvae. In the case of MW, the larvae grew less on the hemp material in comparison to wheat bran. Replacing wheat bran with the hemp material led to smaller larvae with higher Ca, Fe, K, and crude protein content, but lower Mg and P values. No cannabinoids were detected in the MW fed with the hemp material.
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Affiliation(s)
- Wael Yakti
- Urban Plant Ecophysiology Division, Faculty of Life Sciences, Thaer-Institute of Agricultural and Horticultural Sciences, Humboldt-Universität zu Berlin, Lentzeallee 55, 14195 Berlin, Germany
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21
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Combined non-psychoactive Cannabis components cannabidiol and β-caryophyllene reduce chronic pain via CB1 interaction in a rat spinal cord injury model. PLoS One 2023; 18:e0282920. [PMID: 36913400 PMCID: PMC10010563 DOI: 10.1371/journal.pone.0282920] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Accepted: 02/27/2023] [Indexed: 03/14/2023] Open
Abstract
The most frequently reported use of medical marijuana is for pain relief. However, its psychoactive component Δ9-tetrahydrocannabinol (THC) causes significant side effects. Cannabidiol (CBD) and β-caryophyllene (BCP), two other cannabis constituents, possess more benign side effect profiles and are also reported to reduce neuropathic and inflammatory pain. We evaluated the analgesic potential of CBD and BCP individually and in combination in a rat spinal cord injury (SCI) clip compression chronic pain model. Individually, both phytocannabinoids produced dose-dependent reduction in tactile and cold hypersensitivity in male and female rats with SCI. When co-administered at fixed ratios based on individual A50s, CBD and BCP produced enhanced dose-dependent reduction in allodynic responses with synergistic effects observed for cold hypersensitivity in both sexes and additive effects for tactile hypersensitivity in males. Antinociceptive effects of both individual and combined treatment were generally less robust in females than males. CBD:BCP co-administration also partially reduced morphine-seeking behavior in a conditioned place preference (CPP) test. Minimal cannabinoidergic side effects were observed with high doses of the combination. The antinociceptive effects of the CBD:BCP co-administration were not altered by either CB2 or μ-opioid receptor antagonist pretreatment but, were nearly completely blocked by CB1 antagonist AM251. Since neither CBD or BCP are thought to mediate antinociception via CB1 activity, these findings suggest a novel CB1 interactive mechanism between these two phytocannabinoids in the SCI pain state. Together, these findings suggest that CBD:BCP co-administration may provide a safe and effective treatment option for the management of chronic SCI pain.
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22
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Britch SC, Craft RM. Cannabidiol and Delta-9-Tetrahydrocannabinol Interactions in Male and Female Rats With Persistent Inflammatory Pain. THE JOURNAL OF PAIN 2023; 24:98-111. [PMID: 36122809 PMCID: PMC9789172 DOI: 10.1016/j.jpain.2022.09.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Revised: 08/12/2022] [Accepted: 09/01/2022] [Indexed: 02/08/2023]
Abstract
Cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC), 2 of the primary constituents of cannabis, are used by some individuals to self-treat chronic pain. It is unclear whether the pain-relieving effects of CBD alone and in combination with THC are consistent across genders and among types of pain. The present study compared the effects of CBD and THC given alone and in combination in male and female rats with Complete Freund's adjuvant-induced inflammatory pain. After induction of hindpaw inflammation, vehicle, CBD (0.05-2.5 mg/kg), THC (0.05-2.0 mg/kg), or a CBD:THC combination (3:1, 1:1, or 1:3 dose ratio) was administered i.p. twice daily for 3 days. Then on day 4, mechanical allodynia, thermal hyperalgesia, weight-bearing, and locomotor activity were assessed 0.5 to 4 hours after administration of the same dose combination. Hindpaw edema and open field (anxiety-like) behaviors were measured thereafter. THC alone was anti-allodynic and anti-hyperalgesic, and decreased paw thickness, locomotion, and open field behaviors. CBD alone was anti-allodynic and anti-hyperalgesic. When combined with THC, CBD tended to decrease THC effects on pain-related behaviors and exacerbate THC-induced anxiety-like behaviors, particularly in females. These results suggest that at the doses tested, CBD-THC combinations may be less beneficial than THC alone for the treatment of chronic inflammatory pain. PERSPECTIVE: The present study compared CBD and THC effects alone and in combination in male and female rats with persistent inflammatory pain. This study could help clinicians who prescribe cannabis-based medicines for inflammatory pain conditions determine which cannabis constituents may be most beneficial.
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Affiliation(s)
- Stevie C Britch
- Center on Drug and Alcohol Research, University of Kentucky, Lexington, Kentucky; Department of Behavioral Science, University of Kentucky, Lexington, Kentucky.
| | - Rebecca M Craft
- Department of Psychology, Washington State University, Pullman, Washington
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23
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Silva-Cardoso GK, Leite-Panissi CRA. Chronic Pain and Cannabidiol in Animal Models: Behavioral Pharmacology and Future Perspectives. Cannabis Cannabinoid Res 2022; 8:241-253. [PMID: 36355044 DOI: 10.1089/can.2022.0096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
Abstract
The incidence of chronic pain is around 8% in the general population, and its impact on quality of life, mood, and sleep exceeds the burden of its causal pathology. Chronic pain is a complex and multifaceted problem with few effective and safe treatment options. It can be associated with neurological diseases, peripheral injuries or central trauma, or some maladaptation to traumatic or emotional events. In this perspective, animal models are used to assess the manifestations of neuropathy, such as allodynia and hyperalgesia, through nociceptive tests, such as von Frey, Hargreaves, hot plate, tail-flick, Randall & Selitto, and others. Cannabidiol (CBD) has been considered a promising strategy for treating chronic pain and diseases that have pain as a consequence of neuropathy. However, despite the growing body of evidence linking the efficacy of CBD on pain management in clinical and basic research, there is a lack of reviews focusing on chronic pain assessments, especially when considering pre-clinical studies, which assess chronic pain as a disease by itself or as a consequence of trauma or peripheral or central disease. Therefore, this review focused only on studies that fit our inclusion criteria: (1) used treatment with CBD extract; (2) used tests to assess mechanical or thermal nociception in at least one of the following most commonly used tests (von Frey, hot plate, acetone, Hargreaves, tail-flick, Randall & Selitto, and others); and (3) studies that assessed pain sensitivity in chronic pain induction models. The current literature points out that CBD is a well-tolerated and safe natural compound that exerts analgesic effects, decreasing hyperalgesia, and mechanical/thermal allodynia in several animal models of pain and patients. In addition, CBD presents several molecular and cellular mechanisms of action involved in its positive effects on chronic pain. In conclusion, using CBD seems to be a promising strategy to overcome the lack of efficacy of conventional treatment for chronic pain.
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Affiliation(s)
- Gleice Kelli Silva-Cardoso
- Psychology Department, Faculty of Philosophy, Sciences, and Letters of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil
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24
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Dieterle M, Zurbriggen L, Mauermann E, Mercer-Chalmers-Bender K, Frei P, Ruppen W, Schneider T. Pain response to cannabidiol in opioid-induced hyperalgesia, acute nociceptive pain, and allodynia using a model mimicking acute pain in healthy adults in a randomized trial (CANAB II). Pain 2022; 163:1919-1928. [PMID: 35239547 PMCID: PMC9982727 DOI: 10.1097/j.pain.0000000000002591] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 11/25/2021] [Accepted: 12/21/2021] [Indexed: 10/19/2022]
Abstract
ABSTRACT Opioids in general and remifentanil in particular can induce hyperalgesia. Preclinical data suggest that cannabidiol might have the capacity to reduce opioid-induced hyperalgesia (OIH). Thus, we investigated the effect of oral cannabidiol on OIH in healthy volunteers using an established pain model. Twenty-four healthy participants were included in this randomized, double-blinded, crossover study and received either a 1600-mg single-dose oral cannabidiol or placebo. Hyperalgesia, allodynia, and pain were induced by intracutaneous electrical stimulation. To provoke OIH, participants recieved an infusion of 0.1 µg/kg/min remifentanil over a time frame of 30 minutes, starting 100 minutes after oral cannabidiol ingestion. The primary outcome was the area of hyperalgesia (in square centimetres) up to 60 minutes after remifentanil administration. The area of allodynia (in square centimetres) and pain (numeric rating scale) were also assessed.Cannabidiol had no significant effect on hyperalgesia, allodynia, or pain at any time point of measurement compared with placebo. The area of hyperalgesia after remifentanil administration significantly increased compared with baseline (17.0 cm 2 [8.1-28.7] vs 25.3 cm 2 [15.1-39.6]; P = 0.013). Mean cannabidiol blood levels were 4.1 ± 3.0 µg/L (mean ± SD) at 130 minutes after ingestion and were 8.2 μg/L ± 6.9 µg/L (mean ± SD) at 200 minutes. Cannabidiol was well tolerated. We conclude that a high single-oral dose of 1600-mg cannabidiol is not effective in reducing OIH. Before excluding an effect of cannabidiol on OIH, research should focus on drug formulations enabling higher cannabidiol concentrations.
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Affiliation(s)
- Markus Dieterle
- Clinic for Anaesthesia, Intermediate Care, Prehospital Emergency Medicine and Pain Therapy, University Hospital of Basel, Basel, Switzerland
| | - Laura Zurbriggen
- Clinic for Anaesthesia, Intermediate Care, Prehospital Emergency Medicine and Pain Therapy, University Hospital of Basel, Basel, Switzerland
| | - Eckhard Mauermann
- Clinic for Anaesthesia, Intermediate Care, Prehospital Emergency Medicine and Pain Therapy, University Hospital of Basel, Basel, Switzerland
| | | | - Priska Frei
- Institute of Forensic Medicine, Department of Biomedical Engineering, University of Basel, Basel, Switzerland
| | - Wilhelm Ruppen
- Clinic for Anaesthesia, Intermediate Care, Prehospital Emergency Medicine and Pain Therapy, University Hospital of Basel, Basel, Switzerland
| | - Tobias Schneider
- Clinic for Anaesthesia, Intermediate Care, Prehospital Emergency Medicine and Pain Therapy, University Hospital of Basel, Basel, Switzerland
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Kozak JA. Suppression of Store-operated Calcium Entry Channels and Cytokine Release by Cannabinoids. FUNCTION 2022; 3:zqac044. [PMID: 36168590 PMCID: PMC9508850 DOI: 10.1093/function/zqac044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Revised: 08/05/2022] [Accepted: 08/29/2022] [Indexed: 01/07/2023] Open
Affiliation(s)
- J Ashot Kozak
- Department of Neuroscience, Cell Biology and Physiology, Boonshoft School of Medicine and College of Science and Mathematics, Wright State University, Dayton, OH 45435, USA
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Minor Phytocannabinoids: A Misleading Name but a Promising Opportunity for Biomedical Research. Biomolecules 2022; 12:biom12081084. [PMID: 36008978 PMCID: PMC9406211 DOI: 10.3390/biom12081084] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 08/02/2022] [Accepted: 08/04/2022] [Indexed: 12/20/2022] Open
Abstract
Despite the very large number of phytocannabinoids isolated from Cannabis (Cannabis sativa L.), bioactivity studies have long remained focused on the so called “Big Four” [Δ9-THC (1), CBD (2), CBG (3) and CBC (4)] because of their earlier characterization and relatively easy availability via isolation and/or synthesis. Bioactivity information on the chemical space associated with the remaining part of the cannabinome, a set of ca 150 compounds traditionally referred to as “minor phytocannabinoids”, is scarce and patchy, yet promising in terms of pharmacological potential. According to their advancement stage, we sorted the bioactivity data available on these compounds, better referred to as the “dark cannabinome”, into categories: discovery (in vitro phenotypical and biochemical assays), preclinical (animal models), and clinical. Strategies to overcome the availability issues associated with minor phytocannabinoids are discussed, as well as the still unmet challenges facing their development as mainstream drugs.
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Rodriguez CEB, Ouyang L, Kandasamy R. Antinociceptive effects of minor cannabinoids, terpenes and flavonoids in Cannabis. Behav Pharmacol 2022; 33:130-157. [PMID: 33709984 DOI: 10.1097/fbp.0000000000000627] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Cannabis has been used for centuries for its medicinal properties. Given the dangerous and unpleasant side effects of existing analgesics, the chemical constituents of Cannabis have garnered significant interest for their antinociceptive, anti-inflammatory and neuroprotective effects. To date, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) remain the two most widely studied constituents of Cannabis in animals. These studies have led to formulations of THC and CBD for human use; however, chronic pain patients also use different strains of Cannabis (sativa, indica and ruderalis) to alleviate their pain. These strains contain major cannabinoids, such as THC and CBD, but they also contain a wide variety of cannabinoid and noncannabinoid constituents. Although the analgesic effects of Cannabis are attributed to major cannabinoids, evidence indicates other constituents such as minor cannabinoids, terpenes and flavonoids also produce antinociception against animal models of acute, inflammatory, neuropathic, muscle and orofacial pain. In some cases, these constituents produce antinociception that is equivalent or greater compared to that produced by traditional analgesics. Thus, a better understanding of the extent to which these constituents produce antinociception alone in animals is necessary. The purposes of this review are to (1) introduce the different minor cannabinoids, terpenes, and flavonoids found in Cannabis and (2) discuss evidence of their antinociceptive properties in animals.
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Affiliation(s)
- Carl Erwin B Rodriguez
- Department of Psychology, California State University, East Bay, Hayward, California, USA
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28
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Sionov RV, Steinberg D. Anti-Microbial Activity of Phytocannabinoids and Endocannabinoids in the Light of Their Physiological and Pathophysiological Roles. Biomedicines 2022; 10:biomedicines10030631. [PMID: 35327432 PMCID: PMC8945038 DOI: 10.3390/biomedicines10030631] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 03/06/2022] [Accepted: 03/08/2022] [Indexed: 12/12/2022] Open
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 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.
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Short term feeding of industrial hemp with a high cannabidiolic acid (CBDA) content increases lying behavior and reduces biomarkers of stress and inflammation in Holstein steers. Sci Rep 2022; 12:3683. [PMID: 35256692 PMCID: PMC8901777 DOI: 10.1038/s41598-022-07795-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 02/24/2022] [Indexed: 01/17/2023] Open
Abstract
Industrial hemp (IH) is defined as Cannabis sativa containing < 0.3% delta-9 tetrahydrocannabinol (THC) and was legalized in the 2018 Farm Bill. The impact of cannabinoids in IH fed to livestock, especially after repeat exposure, has not been thoroughly investigated. Sixteen male castrated Holstein cattle weighting (± SD) 447 ± 68 kg were enrolled onto the study. Cattle were allocated into two treatment groups either receiving IH (HEMP, n = 8) or a control (CNTL, n = 8). Cattle in the HEMP group were fed 25 g IH mixed in 200 g of grain once a day for 14 days to target a daily dose of 5.5 mg/kg of cannabidiolic acid (CBDA). Behavior was continuously monitored with accelerometers and blood samples were collected at predetermined time points for plasma cannabinoid, serum cortisol, serum haptoglobin, liver enzymes, serum amyloid A, and prostaglandin E2 concentrations. The HEMP group spent a mean 14.1 h/d (95% CI 13.6–14.6 h/d) lying compared to the 13.4 h/d (95% CI 12.9–13.8 h/d) for the CNTL cattle (P = 0.03). Cortisol concentrations in the HEMP group were lower than the CNTL group (P = 0.001). Cattle in the HEMP group demonstrated an 8.8% reduction in prostaglandin E2 concentrations from baseline compared to a 10.2% increase from baseline observed in the CNTL group. No differences for haptoglobin or serum amyloid A were observed. These results suggest that feeding IH with a high CBDA content for 14 days increases lying behavior and decreases biomarkers of stress and inflammation in cattle.
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DeVuono MV, La Caprara O, Petrie GN, Limebeer CL, Rock EM, Hill MN, Parker LA. Cannabidiol Interferes with Establishment of Δ 9-Tetrahydrocannabinol-Induced Nausea Through a 5-HT 1A Mechanism. Cannabis Cannabinoid Res 2022; 7:58-64. [PMID: 33998876 PMCID: PMC8864431 DOI: 10.1089/can.2020.0083] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Introduction: Cannabinoid hyperemesis syndrome (CHS) is characterized by intense nausea and vomiting brought on by the use of high-dose Δ9-tetrahydrocannabinol (THC), the main psychotropic compound in cannabis. Cannabidiol (CBD), a nonpsychotropic compound found in cannabis, has been shown to interfere with some acute aversive effects of THC. In this study, we evaluated if CBD would interfere with THC-induced nausea through a 5-HT1A receptor mechanism as it has been shown to interfere with nausea produced by lithium chloride (LiCl). Since CHS has been attributed to a dysregulated stress response, we also evaluated if CBD would interfere with THC-induced increase in corticosterone (CORT). Materials and Methods: The potential of CBD (5 mg/kg, ip) to suppress THC-induced conditioned gaping (a measure of nausea) was evaluated in rats, as well as the potential of the 5-HT1A receptor antagonist, WAY-100635 (WAY; 0.1 mg/kg, ip), to reverse the suppression of THC-induced conditioned gaping by CBD. Last, the effect of CBD (5 mg/kg, ip) on THC-induced increase in serum CORT concentration was evaluated. Results: Pretreatment with CBD (5 mg/kg, ip) interfered with the establishment of THC-induced conditioned gaping (p=0.007, relative to vehicle [VEH] pretreatment), and this was reversed by pretreatment with 0.1 mg/kg WAY. This dose of WAY had no effect on gaping on its own. THC (10 mg/kg, ip) significantly increased serum CORT compared with VEH-treated rats (p=0.04). CBD (5 mg/kg, ip) pretreatment reversed the THC-induced increase in CORT. Conclusions: CBD attenuated THC-induced nausea as well as THC-induced elevation in CORT. The attenuation of THC-induced conditioned gaping by CBD was mediated by its action on 5-HT1A receptors, similar to that of LiCl-induced nausea.
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Affiliation(s)
- Marieka V. DeVuono
- Department of Psychology and Collaborative Neuroscience Program, University of Guelph, Guelph, Canada
| | - Olivia La Caprara
- Department of Psychology and Collaborative Neuroscience Program, University of Guelph, Guelph, Canada
| | - Gavin N. Petrie
- Department of Cell Biology and Anatomy, Hotchkiss Brain Institute, University of Calgary, Calgary, Canada.,Department of Psychiatry, Hotchkiss Brain Institute, University of Calgary, Calgary, Canada
| | - Cheryl L. Limebeer
- Department of Psychology and Collaborative Neuroscience Program, University of Guelph, Guelph, Canada
| | - Erin M. Rock
- Department of Psychology and Collaborative Neuroscience Program, University of Guelph, Guelph, Canada
| | - Matthew N. Hill
- Department of Cell Biology and Anatomy, Hotchkiss Brain Institute, University of Calgary, Calgary, Canada.,Department of Psychiatry, Hotchkiss Brain Institute, University of Calgary, Calgary, Canada
| | - Linda A. Parker
- Department of Psychology and Collaborative Neuroscience Program, University of Guelph, Guelph, Canada.,*Address correspondence to: Linda A. Parker, PhD, Department of Psychology and Collaborative Neuroscience Program, University of Guelph, Guelph, ON N1G 2W1, Canada,
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31
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Cannabidiol but not cannabidiolic acid reduces behavioural sensitisation to methamphetamine in rats, at pharmacologically effective doses. Psychopharmacology (Berl) 2022; 239:1593-1603. [PMID: 35435462 PMCID: PMC9110442 DOI: 10.1007/s00213-022-06119-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Accepted: 03/14/2022] [Indexed: 11/24/2022]
Abstract
RATIONALE Cannabidiol (CBD) and cannabidiolic acid (CBDA) are non-psychoactive components of the cannabis plant. CBD has been well characterised to have anxiolytic and anticonvulsant activity, whereas the behavioural effects of CBDA are less clear. Preclinical and clinical data suggests that CBD has antipsychotic properties and reduces methamphetamine self-administration in rats. An animal model that is commonly used to mimic the neurochemical changes underlying psychosis and drug dependence is methamphetamine (METH) sensitisation, where repeated administration of the psychostimulant progressively increases the locomotor effects of METH. OBJECTIVE The aim of this study was to determine whether CBD or CBDA attenuate METH-induced sensitisation of locomotor hyperactivity in rats. METHODS Eighty-six male Sprague Dawley rats underwent METH sensitisation protocol where they were subjected to daily METH (1 mg/kg on days 2 and 8, 5 mg/kg on days 3-7; i.p.) injections for 7 days. After 21 days of withdrawal, rats were given a prior injection of CBD (0, 40 and 80 mg/kg; i.p.) or CBDA (0, 0.1, 10 and 1000 µg/kg; i.p.) and challenged with acute METH (1 mg/kg; i.p.). Locomotor activity was then measured for 60 min. RESULTS Rats displayed robust METH sensitisation as evidenced by increased locomotor activity to METH challenge in METH-pretreated versus SAL-pretreated rats. CBD (40 and 80 mg/kg) reduced METH-induced sensitisation. There was no effect of any CBDA doses on METH sensitisation or acute METH-induced hyperactivity. CONCLUSION These results demonstrate that CBD, but not CBDA, reduces METH sensitisation of locomotor activity in rats at pharmacologically effective doses, thus reinforcing evidence that CBD has anti-addiction and antipsychotic properties.
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32
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Boulebd H. Is cannabidiolic acid an overlooked natural antioxidant? Insights from quantum chemistry calculations. NEW J CHEM 2022. [DOI: 10.1039/d1nj04771j] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The radical scavenging capacity of CBDA is moderate in lipid media but it is very important in water via the SET mechanism.
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Affiliation(s)
- Houssem Boulebd
- Laboratory of Synthesis of Molecules with Biological Interest, University of Frères Mentouri Constantine 1, Constantine, Algeria
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Walsh KB, McKinney AE, Holmes AE. Minor Cannabinoids: Biosynthesis, Molecular Pharmacology and Potential Therapeutic Uses. Front Pharmacol 2021; 12:777804. [PMID: 34916950 PMCID: PMC8669157 DOI: 10.3389/fphar.2021.777804] [Citation(s) in RCA: 74] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Accepted: 11/08/2021] [Indexed: 11/29/2022] Open
Abstract
The medicinal use of Cannabis sativa L. can be traced back thousands of years to ancient China and Egypt. While marijuana has recently shown promise in managing chronic pain and nausea, scientific investigation of cannabis has been restricted due its classification as a schedule 1 controlled substance. A major breakthrough in understanding the pharmacology of cannabis came with the isolation and characterization of the phytocannabinoids trans-Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD). This was followed by the cloning of the cannabinoid CB1 and CB2 receptors in the 1990s and the subsequent discovery of the endocannabinoid system. In addition to the major phytocannabinoids, Δ9-THC and CBD, cannabis produces over 120 other cannabinoids that are referred to as minor and/or rare cannabinoids. These cannabinoids are produced in smaller amounts in the plant and are derived along with Δ9-THC and CBD from the parent cannabinoid cannabigerolic acid (CBGA). While our current knowledge of minor cannabinoid pharmacology is incomplete, studies demonstrate that they act as agonists and antagonists at multiple targets including CB1 and CB2 receptors, transient receptor potential (TRP) channels, peroxisome proliferator-activated receptors (PPARs), serotonin 5-HT1a receptors and others. The resulting activation of multiple cell signaling pathways, combined with their putative synergistic activity, provides a mechanistic basis for their therapeutic actions. Initial clinical reports suggest that these cannabinoids may have potential benefits in the treatment of neuropathic pain, neurodegenerative diseases, epilepsy, cancer and skin disorders. This review focuses on the molecular pharmacology of the minor cannabinoids and highlights some important therapeutic uses of the compounds.
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Affiliation(s)
- Kenneth B Walsh
- Department of Pharmacology, Physiology and Neuroscience, School of Medicine, University of South Carolina, Columbia, SC, United States
| | - Amanda E McKinney
- Institute for Human and Planetary Health, Crete, NE, United States.,School of Integrative Learning, Doane University, Crete, NE, United States
| | - Andrea E Holmes
- School of Integrative Learning, Doane University, Crete, NE, United States.,Precision Plant Molecules, Denver, CO, United States
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Williams MR, Holbrook TC, Maxwell L, Croft CH, Ientile MM, Cliburn K. Pharmacokinetic Evaluation of a Cannabidiol Supplement in Horses. J Equine Vet Sci 2021; 110:103842. [PMID: 34923070 DOI: 10.1016/j.jevs.2021.103842] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 11/01/2021] [Accepted: 12/13/2021] [Indexed: 12/31/2022]
Abstract
Cannabidiol (CBD) products have gained popularity among horse owners despite limited evidence regarding pharmacokinetics. The purpose of this study was to describe the pharmacokinetic profile of multiple doses of an orally administered cannabidiol product formulated specifically for horses. A randomized 2-way crossover design was used. Seven horses received 0.35 or 2.0 mg/kg CBD per os every 24 hours for 7 total doses, separated by a 2-week washout. Plasma CBD and delta-9-tetrahydrocannabinol (THC) were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS) daily through day 10, then on day 14 after beginning CBD administration. On the final day of CDB administration, plasma CBD and THC were quantified at multiple times. After administration of 0.35 mg/kg of CDB, the Cmax of CBD was 6.6 ± 2.1 ng/mL while Tmax was 1.8 ± 1.2 hour, whereas the Cmax for THC was 0.7 ± 0.6 ng/mL with a Tmax of 2.5 ± 1 hour. After administration of 2.0 mg/kg of CBD, the Cmax of CBD was 51 ± 14 ng/mL with a mean Tmax of 2.4 ± 1.1 hour and terminal phase half-life of 10.4 ± 6 hour, whereas the Cmax of THC was 7.5 ± 2.2 ng/mL with a Tmax of 2.9 ± 1.1 hour. Oral administration of a cannabidiol product at 0.35 mg/kg or 2.0 mg/kg once daily for 7 days was well-tolerated. Based on plasma CBD levels obtained, dose escalation trials in the horse evaluating clinical efficacy at higher mg/kg dose rates are indicated.
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Affiliation(s)
- Megan R Williams
- Department of Veterinary Clinical Sciences, Oklahoma State University, Stillwater, OK 74078.
| | - Todd C Holbrook
- Department of Veterinary Clinical Sciences, Oklahoma State University, Stillwater, OK 74078; Department of Veterinary Clinical Sciences, University of Florida, Gainesville, FL 32610
| | - Lara Maxwell
- Department of Veterinary Clinical Sciences, Oklahoma State University, Stillwater, OK 74078
| | - Cara H Croft
- Department of Veterinary Clinical Sciences, Oklahoma State University, Stillwater, OK 74078
| | - Michelle M Ientile
- Department of Veterinary Clinical Sciences, Oklahoma State University, Stillwater, OK 74078
| | - Kacey Cliburn
- Office of the Chief Medical Examiner, Oklahoma City, OK 73105
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35
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Britch SC, Craft RM. No antinociceptive synergy between morphine and delta-9-tetrahydrocannabinol in male and female rats with persistent inflammatory pain. Behav Pharmacol 2021; 32:630-639. [PMID: 34561365 PMCID: PMC8578411 DOI: 10.1097/fbp.0000000000000657] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Studies have demonstrated antinociceptive synergy between morphine and delta-9-tetrahydrocannabinol (THC) in animals, but whether such synergy occurs against all types of pain and in humans is unclear. Because a majority of chronic pain patients are women, and sex differences in morphine and THC potencies have been observed in rodents, the present study examined sex-specific effects of morphine and THC given alone and in combination, in rats with persistent inflammatory pain. On day 1, baseline mechanical and thermal response thresholds, hindpaw weight-bearing, locomotor activity, and hindpaw thickness were determined. Inflammation was then induced via hindpaw injection of complete Freund's adjuvant (CFA). Three days later, morphine (s.c.), THC (i.p) or a morphine-THC combination (1:1, 3:1 and 1:3 dose ratios) was administered, and behavioral testing was conducted at 30-240 min postinjection. Morphine alone was antiallodynic and antihyperalgesic, with no sex differences, but at some doses increased weight-bearing on the CFA-treated paw more in males than females. THC alone reduced mechanical allodynia with similar potency in both sexes, but reduced thermal hyperalgesia and locomotor activity with greater potency in females than males. All morphine-THC combinations reduced allodynia and hyperalgesia, but isobolographic analysis of mechanical allodynia data showed no significant morphine-THC synergy in either sex. Additionally, whereas morphine alone was antinociceptive at doses that did not suppress locomotion, morphine-THC combinations suppressed locomotion and did not increase weight-bearing on the inflamed paw. These results suggest that THC is unlikely to be a beneficial adjuvant when given in combination with morphine for reducing established inflammatory pain.
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Affiliation(s)
- Stevie C Britch
- Center on Drug and Alcohol Research, University of Kentucky
- Department of Behavioral Science, University of Kentucky, Lexington, Kentucky
| | - Rebecca M Craft
- Department of Psychology, Washington State University, Pullman, Washington, USA
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Analgesic and Anti-Inflammatory Activities of Sophocarpine from Sophora viciifolia Hance. BIOMED RESEARCH INTERNATIONAL 2021; 2021:8893563. [PMID: 34790825 PMCID: PMC8592712 DOI: 10.1155/2021/8893563] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/26/2020] [Revised: 07/12/2021] [Accepted: 10/07/2021] [Indexed: 11/17/2022]
Abstract
Sophora viciifolia Hance is an edible plant used in traditional Chinese medicine. Sophocarpine, a tetracyclic quinolizidine alkaloid, is one of the most abundant active ingredients in Sophora viciifolia Hance. Here, we study the analgesic and anti-inflammatory effects, as well as the acute toxicity of sophocarpine from Sophora viciifolia Hance in mice. Sophocarpine (20, 40, and 80 mg/kgbw) significantly prolonged the delay period before a hot plate reaction occurred (all P < 0.05), and the delay before a tail-flick response was induced by a warm bath (P < 0.05; P < 0.01). Sophocarpine (40, 80 mg/kg) resulted in dose-dependent inhibition of the writhing reaction induced by acetic acid in mice (P < 0.05; P < 0.001, respectively). Sophocarpine (80 mg/kg) reduced the total duration of a formalin-induced pain response (P < 0.05). Sophocarpine prolonged the foot-licking latency of mice after the hot plate reaction, and this effect was antagonized by calcium chloride and enhanced by verapamil. Sophocarpine (20, 40, and 80 mg/kg) significantly inhibited xylene-induced ear edema (P < 0.01; P < 0.001; P < 0.001, respectively) and the penetration of acetic acid-induced dye into the peritoneal cavity (P < 0.01; P < 0.01; P < 0.001, respectively). It also reduced the levels of proinflammatory cytokine interleukin (IL)-1β, IL-6, and prostaglandin E2 (P < 0.05, P < 0.01, P < 0.001) and those of serum nitric oxide (P < 0.05). The results of this study suggest that sophocarpine possesses certain analgesic and anti-inflammatory activities, which may be related to calcium and inhibition of the secretion of inflammatory factors.
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37
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Major Phytocannabinoids and Their Related Compounds: Should We Only Search for Drugs That Act on Cannabinoid Receptors? Pharmaceutics 2021; 13:pharmaceutics13111823. [PMID: 34834237 PMCID: PMC8625816 DOI: 10.3390/pharmaceutics13111823] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 10/24/2021] [Accepted: 10/25/2021] [Indexed: 12/24/2022] Open
Abstract
The most important discoveries in pharmacology, such as certain classes of analgesics or chemotherapeutics, started from natural extracts which have been found to have effects in traditional medicine. Cannabis, traditionally used in Asia for the treatment of pain, nausea, spasms, sleep, depression, and low appetite, is still a good candidate for the development of new compounds. If initially all attention was directed to the endocannabinoid system, recent studies suggest that many of the clinically proven effects are based on an intrinsic chain of mechanisms that do not necessarily involve only cannabinoid receptors. Recent research has shown that major phytocannabinoids and their derivatives also interact with non-cannabinoid receptors such as vanilloid receptor 1, transient receptor ankyrin 1 potential, peroxisome proliferator-activated receptor-gamma or glitazone receptor, G55 protein-coupled receptor, and nuclear receptor, producing pharmacological effects in diseases such as Alzheimer's, epilepsy, depression, neuropathic pain, cancer, and diabetes. Nonetheless, further studies are needed to elucidate the precise mechanisms of these compounds. Structure modulation of phytocannabinoids, in order to improve pharmacological effects, should not be limited to the exploration of cannabinoid receptors, and it should target other courses of action discovered through recent research.
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38
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Anderson LL, Heblinski M, Absalom NL, Hawkins NA, Bowen M, Benson MJ, Zhang F, Bahceci D, Doohan PT, Chebib M, McGregor IS, Kearney JA, Arnold JC. Cannabigerolic acid, a major biosynthetic precursor molecule in cannabis, exhibits divergent effects on seizures in mouse models of epilepsy. Br J Pharmacol 2021; 178:4826-4841. [PMID: 34384142 PMCID: PMC9292928 DOI: 10.1111/bph.15661] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 07/26/2021] [Accepted: 08/10/2021] [Indexed: 11/28/2022] Open
Abstract
Background and Purpose Cannabis has been used to treat epilepsy for millennia, with such use validated by regulatory approval of cannabidiol (CBD) for Dravet syndrome. Unregulated artisanal cannabis‐based products used to treat children with intractable epilepsies often contain relatively low doses of CBD but are enriched in other phytocannabinoids. This raises the possibility that other cannabis constituents might have anticonvulsant properties. Experimental Approach We used the Scn1a+/− mouse model of Dravet syndrome to investigate the cannabis plant for phytocannabinoids with anticonvulsant effects against hyperthermia‐induced seizures. The most promising, cannabigerolic acid (CBGA), was further examined against spontaneous seizures and survival in Scn1a+/− mice and in electroshock seizure models. Pharmacological effects of CBGA were surveyed across multiple drug targets. Key Results The initial screen identified three phytocannabinoids with novel anticonvulsant properties: CBGA, cannabidivarinic acid (CBDVA) and cannabigerovarinic acid (CBGVA). CBGA was most potent and potentiated the anticonvulsant effects of clobazam against hyperthermia‐induced and spontaneous seizures, and was anticonvulsant in the MES threshold test. However, CBGA was proconvulsant in the 6‐Hz threshold test and a high dose increased spontaneous seizure frequency in Scn1a+/− mice. CBGA was found to interact with numerous epilepsy‐relevant targets including GPR55, TRPV1 channels and GABAA receptors. Conclusion and Implications These results suggest that CBGA, CBDVA and CBGVA may contribute to the effects of cannabis‐based products in childhood epilepsy. Although these phytocannabinoids have anticonvulsant potential and could be lead compounds for drug development programmes, several liabilities would need to be overcome before CBD is superseded by another in this class.
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Affiliation(s)
- L L Anderson
- Lambert Initiative for Cannabinoid Therapeutics, The University of Sydney, Sydney, New South Wales, Australia.,Discipline of Pharmacology, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.,School of Pharmacy, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.,Brain and Mind Centre, The University of Sydney, Sydney, New South Wales, Australia
| | - M Heblinski
- Lambert Initiative for Cannabinoid Therapeutics, The University of Sydney, Sydney, New South Wales, Australia.,Discipline of Pharmacology, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.,Brain and Mind Centre, The University of Sydney, Sydney, New South Wales, Australia
| | - N L Absalom
- School of Pharmacy, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.,Brain and Mind Centre, The University of Sydney, Sydney, New South Wales, Australia
| | - N A Hawkins
- Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America
| | - M Bowen
- Lambert Initiative for Cannabinoid Therapeutics, The University of Sydney, Sydney, New South Wales, Australia.,School of Psychology, Faculty of Science, The University of Sydney, Sydney, New South Wales, Australia
| | - M J Benson
- Lambert Initiative for Cannabinoid Therapeutics, The University of Sydney, Sydney, New South Wales, Australia.,Brain and Mind Centre, The University of Sydney, Sydney, New South Wales, Australia.,School of Psychology, Faculty of Science, The University of Sydney, Sydney, New South Wales, Australia
| | - F Zhang
- School of Pharmacy, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
| | - D Bahceci
- Lambert Initiative for Cannabinoid Therapeutics, The University of Sydney, Sydney, New South Wales, Australia.,Discipline of Pharmacology, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.,Brain and Mind Centre, The University of Sydney, Sydney, New South Wales, Australia
| | - P T Doohan
- Lambert Initiative for Cannabinoid Therapeutics, The University of Sydney, Sydney, New South Wales, Australia.,Discipline of Pharmacology, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.,Brain and Mind Centre, The University of Sydney, Sydney, New South Wales, Australia
| | - M Chebib
- School of Pharmacy, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.,Brain and Mind Centre, The University of Sydney, Sydney, New South Wales, Australia
| | - I S McGregor
- Lambert Initiative for Cannabinoid Therapeutics, The University of Sydney, Sydney, New South Wales, Australia.,Brain and Mind Centre, The University of Sydney, Sydney, New South Wales, Australia.,School of Psychology, Faculty of Science, The University of Sydney, Sydney, New South Wales, Australia
| | - J A Kearney
- Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America
| | - J C Arnold
- Lambert Initiative for Cannabinoid Therapeutics, The University of Sydney, Sydney, New South Wales, Australia.,Discipline of Pharmacology, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.,School of Pharmacy, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.,Brain and Mind Centre, The University of Sydney, Sydney, New South Wales, Australia
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39
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Anderson LL, Etchart MG, Bahceci D, Golembiewski TA, Arnold JC. Cannabis constituents interact at the drug efflux pump BCRP to markedly increase plasma cannabidiolic acid concentrations. Sci Rep 2021; 11:14948. [PMID: 34294753 PMCID: PMC8298633 DOI: 10.1038/s41598-021-94212-6] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 06/25/2021] [Indexed: 12/19/2022] Open
Abstract
Cannabis is a complex mixture of hundreds of bioactive molecules. This provides the potential for pharmacological interactions between cannabis constituents, a phenomenon referred to as “the entourage effect” by the medicinal cannabis community. We hypothesize that pharmacokinetic interactions between cannabis constituents could substantially alter systemic cannabinoid concentrations. To address this hypothesis we compared pharmacokinetic parameters of cannabinoids administered orally in a cannabis extract to those administered as individual cannabinoids at equivalent doses in mice. Astonishingly, plasma cannabidiolic acid (CBDA) concentrations were 14-times higher following administration in the cannabis extract than when administered as a single molecule. In vitro transwell assays identified CBDA as a substrate of the drug efflux transporter breast cancer resistance protein (BCRP), and that cannabigerol and Δ9-tetrahydrocannabinol inhibited the BCRP-mediated transport of CBDA. Such a cannabinoid-cannabinoid interaction at BCRP transporters located in the intestine would inhibit efflux of CBDA, thus resulting in increased plasma concentrations. Our results suggest that cannabis extracts provide a natural vehicle to substantially enhance plasma CBDA concentrations. Moreover, CBDA might have a more significant contribution to the pharmacological effects of orally administered cannabis extracts than previously thought.
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Affiliation(s)
- Lyndsey L Anderson
- Brain and Mind Centre, Discipline of Pharmacology, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia.,Lambert Initiative for Cannabinoid Therapeutics, Brain and Mind Centre, The University of Sydney, 94 Mallett St, Camperdown, NSW, 2050, Australia
| | - Maia G Etchart
- Lambert Initiative for Cannabinoid Therapeutics, Brain and Mind Centre, The University of Sydney, 94 Mallett St, Camperdown, NSW, 2050, Australia
| | - Dilara Bahceci
- Brain and Mind Centre, Discipline of Pharmacology, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
| | - Taliesin A Golembiewski
- Brain and Mind Centre, Discipline of Pharmacology, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia
| | - Jonathon C Arnold
- Brain and Mind Centre, Discipline of Pharmacology, Faculty of Medicine and Health, The University of Sydney, Sydney, Australia. .,Lambert Initiative for Cannabinoid Therapeutics, Brain and Mind Centre, The University of Sydney, 94 Mallett St, Camperdown, NSW, 2050, Australia.
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40
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Arif Y, Singh P, Bajguz A, Hayat S. Phytocannabinoids Biosynthesis in Angiosperms, Fungi, and Liverworts and Their Versatile Role. PLANTS (BASEL, SWITZERLAND) 2021; 10:1307. [PMID: 34203173 PMCID: PMC8309193 DOI: 10.3390/plants10071307] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/06/2021] [Revised: 06/22/2021] [Accepted: 06/25/2021] [Indexed: 11/16/2022]
Abstract
Phytocannabinoids are a structurally diverse class of bioactive naturally occurring compounds found in angiosperms, fungi, and liverworts and produced in several plant organs such as the flower and glandular trichrome of Cannabis sativa, the scales in Rhododendron, and oil bodies of liverworts such as Radula species; they show a diverse role in humans and plants. Moreover, phytocannabinoids are prenylated polyketides, i.e., terpenophenolics, which are derived from isoprenoid and fatty acid precursors. Additionally, targeted productions of active phytocannabinoids have beneficial properties via the genes involved and their expression in a heterologous host. Bioactive compounds show a remarkable non-hallucinogenic biological property that is determined by the variable nature of the side chain and prenyl group defined by the enzymes involved in their biosynthesis. Phytocannabinoids possess therapeutic, antibacterial, and antimicrobial properties; thus, they are used in treating several human diseases. This review gives the latest knowledge on their role in the amelioration of abiotic (heat, cold, and radiation) stress in plants. It also aims to provide synthetic and biotechnological approaches based on combinatorial biochemical and protein engineering to synthesize phytocannabinoids with enhanced properties.
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Affiliation(s)
- Yamshi Arif
- Department of Botany, Plant Physiology Section, Faculty of Life Sciences, Aligarh Muslim University, Aligarh 202002, India; (Y.A.); (P.S.); (S.H.)
| | - Priyanka Singh
- Department of Botany, Plant Physiology Section, Faculty of Life Sciences, Aligarh Muslim University, Aligarh 202002, India; (Y.A.); (P.S.); (S.H.)
| | - Andrzej Bajguz
- Department of Biology and Plant Ecology, Faculty of Biology, University of Bialystok, Ciolkowskiego 1J, 15-245 Bialystok, Poland
| | - Shamsul Hayat
- Department of Botany, Plant Physiology Section, Faculty of Life Sciences, Aligarh Muslim University, Aligarh 202002, India; (Y.A.); (P.S.); (S.H.)
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41
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Cannabidiol Inhibition of Murine Primary Nociceptors: Tight Binding to Slow Inactivated States of Na v1.8 Channels. J Neurosci 2021; 41:6371-6387. [PMID: 34131037 DOI: 10.1523/jneurosci.3216-20.2021] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2020] [Revised: 05/11/2021] [Accepted: 06/04/2021] [Indexed: 02/06/2023] Open
Abstract
The nonpsychoactive phytocannabinoid cannabidiol (CBD) has been shown to have analgesic effects in animal studies but little is known about its mechanism of action. We examined the effects of CBD on intrinsic excitability of primary pain-sensing neurons. Studying acutely dissociated capsaicin-sensitive mouse DRG neurons at 37°C, we found that CBD effectively inhibited repetitive action potential firing, from 15-20 action potentials evoked by 1 s current injections in control to 1-3 action potentials with 2 μm CBD. Reduction of repetitive firing was accompanied by a reduction of action potential height, widening of action potentials, reduction of the afterhyperpolarization, and increased propensity to enter depolarization block. Voltage-clamp experiments showed that CBD inhibited both TTX-sensitive and TTX-resistant (TTX-R) sodium currents in a use-dependent manner. CBD showed strong state-dependent inhibition of TTX-R channels, with fast binding to inactivated channels during depolarizations and slow unbinding on repolarization. CBD alteration of channel availability at various voltages suggested that CBD binds especially tightly [K d (dissociation constant), ∼150 nm] to the slow inactivated state of TTX-R channels, which can be substantially occupied at voltages as negative as -40 mV. Remarkably, CBD was more potent in inhibiting TTX-R channels and inhibiting action potential firing than the local anesthetic bupivacaine. We conclude that CBD might produce some of its analgesic effects by direct effects on neuronal excitability, with tight binding to the slow inactivated state of Nav1.8 channels contributing to effective inhibition of repetitive firing by modest depolarizations.SIGNIFICANCE STATEMENT Cannabidiol (CBD) has been shown to inhibit pain in various rodent models, but the mechanism of this effect is unknown. We describe the ability of CBD to inhibit repetitive action potential firing in primary nociceptive neurons from mouse dorsal root ganglia and analyze the effects on voltage-dependent sodium channels. We find that CBD interacts with TTX-resistant sodium channels in a state-dependent manner suggesting particularly tight binding to slow inactivated states of Nav1.8 channels, which dominate the overall inactivation of Nav1.8 channels for small maintained depolarizations from the resting potential. The results suggest that CBD can exert analgesic effects in part by directly inhibiting repetitive firing of primary nociceptors and suggest a strategy of identifying compounds that bind selectively to slow inactivated states of Nav1.8 channels for developing effective analgesics.
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42
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Schlag AK, O'Sullivan SE, Zafar RR, Nutt DJ. Current controversies in medical cannabis: Recent developments in human clinical applications and potential therapeutics. Neuropharmacology 2021; 191:108586. [PMID: 33940011 DOI: 10.1016/j.neuropharm.2021.108586] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 04/20/2021] [Accepted: 04/25/2021] [Indexed: 12/15/2022]
Abstract
Knowledge about the therapeutic potential of medical cannabis has greatly improved over the past decade, with an ever-increasing range of developments in human clinical applications. A growing body of scientific evidence supports the use of medical cannabis products for some therapeutic indications, whilst for others, the evidence base remains disputed. For this narrative review, we incorporate areas where the current evidence base is substantial, such as intractable childhood epilepsy and multiple sclerosis, as well as areas where the evidence is still controversial, such as PTSD and anxiety. We provide a high-level summary of current developments using findings from recent major reviews, as well as real world evidence (RWE), including global database registries and other patient reported outcomes (PROs). On the one hand, our strongest empirical data supports the use of cannabis-based medicinal products (CBMPs) for conditions with relatively small patient numbers. Yet on the other hand, the conditions, where the highest patient numbers present, often have debatable clinical evidence but good RWE, incorporating PROs of 1000s of patients. The discord between PROs and the respective strength of the evidence from randomised controlled trials (RCTs) highlights the urgent need for further research. The scientific literature examining the efficacy of medical cannabis for many conditions is still developing, whilst large numbers of patients globally have been successfully using medical cannabis to treat a broad range of conditions. We conclude on the importance of systematically developing RWE databases to supplement RCTs and to bridge the current evidence gaps.
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Affiliation(s)
- Anne Katrin Schlag
- Drug Science, London, UK; Imperial College London, Du Cane Road, London, W12 0NN, UK.
| | | | - Rayyan R Zafar
- Drug Science, London, UK; Imperial College London, Du Cane Road, London, W12 0NN, UK.
| | - David J Nutt
- Drug Science, London, UK; Imperial College London, Du Cane Road, London, W12 0NN, UK.
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43
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Mabou Tagne A, Fotio Y, Lin L, Squire E, Ahmed F, Rashid TI, Karimian Azari E, Piomelli D. Palmitoylethanolamide and hemp oil extract exert synergistic anti-nociceptive effects in mouse models of acute and chronic pain. Pharmacol Res 2021; 167:105545. [PMID: 33722712 DOI: 10.1016/j.phrs.2021.105545] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 03/08/2021] [Accepted: 03/09/2021] [Indexed: 12/15/2022]
Abstract
The use of products derived from hemp - i.e., cannabis varieties with low Δ9-tetrahydrocannabinol (Δ9-THC) content - as self-medication for pain and other health conditions is gaining in popularity but preclinical and clinical evidence for their effectiveness remains very limited. In the present study, we assessed the efficacy of a full-spectrum hemp oil extract (HOE; 10, 50 and 100 mg-kg-1; oral route), alone or in combination with the anti-inflammatory and analgesic agent palmitoylethanolamide (PEA; 10, 30, 100 and 300 mg-kg-1; oral route), in the formalin and chronic constriction injury (CCI) tests. We found that HOE exerts modest antinociceptive effects when administered alone, whereas the combination of sub-effective oral doses of HOE and PEA produces a substantial greater-than-additive alleviation of pain-related behaviors. Transcription of interleukin (IL)-6 and IL-10 increased significantly in lumbar spinal cord tissue on day 7 after CCI surgery, an effect that was attenuated to the same extent by HOE alone or by the HOE/PEA combination. Pharmacokinetic experiments show that co-administration of HOE enhances and prolongs systemic exposure to PEA. Collectively, our studies lend support to possible beneficial effects of using HOE in combination with PEA to treat acute and chronic pain.
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Affiliation(s)
- Alex Mabou Tagne
- Department of Anatomy and Neurobiology, University of California, Irvine, CA 92697-4625, USA
| | - Yannick Fotio
- Department of Anatomy and Neurobiology, University of California, Irvine, CA 92697-4625, USA
| | - Lin Lin
- Department of Anatomy and Neurobiology, University of California, Irvine, CA 92697-4625, USA
| | - Erica Squire
- Department of Anatomy and Neurobiology, University of California, Irvine, CA 92697-4625, USA
| | - Faizy Ahmed
- Department of Anatomy and Neurobiology, University of California, Irvine, CA 92697-4625, USA
| | - Tarif Ibne Rashid
- Department of Anatomy and Neurobiology, University of California, Irvine, CA 92697-4625, USA
| | | | - Daniele Piomelli
- Department of Anatomy and Neurobiology, University of California, Irvine, CA 92697-4625, USA; Department of Biological Chemistry, University of California, Irvine, CA 92697-4625, USA; Department of Pharmaceutical Sciences, University of California, Irvine, CA 92697-4625, USA.
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Rock EM, Parker LA. Constituents of Cannabis Sativa. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1264:1-13. [PMID: 33332000 DOI: 10.1007/978-3-030-57369-0_1] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The Cannabis sativa plant has been used medicinally and recreationally for thousands of years, but recently only relatively some of its constituents have been identified. There are more than 550 chemical compounds in cannabis, with more than 100 phytocannabinoids being identified, including Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). These phytocannabinoids work by binding to the cannabinoid receptors, as well as other receptor systems. Also within cannabis are the aromatic terpenes, more than 100 of which have been identified. Cannabis and its constituents have been indicated as therapeutic compounds in numerous medical conditions, such as pain, anxiety, epilepsy, nausea and vomiting, and post-traumatic stress disorder. This chapter provides an overview of some of the biological effects of a number of the cannabinoids and terpenes, as well as discussing their known mechanisms of action and evidence of potential therapeutic effects.
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Affiliation(s)
- Erin M Rock
- Department of Psychology and Collaborative Neuroscience Program, University of Guelph, Guelph, ON, Canada
| | - Linda A Parker
- Department of Psychology and Collaborative Neuroscience Program, University of Guelph, Guelph, ON, Canada.
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Neuromolecular Mechanisms of Cannabis Action. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1264:15-28. [PMID: 33332001 DOI: 10.1007/978-3-030-57369-0_2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Most of our current understanding of the neuromolecular mechanisms of Cannabis action focusses on two plant cannabinoids, THC and CBD. THC acts primarily through presynaptic CB cannabinoid receptors to regulate neurotransmitter release in the brain, spinal cord and peripheral nerves. CBD action, on the other hand, is probably mediated through multiple molecular targets.
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Alkislar I, Miller AR, Hohmann AG, Sadaka AH, Cai X, Kulkarni P, Ferris CF. Inhaled Cannabis Suppresses Chemotherapy-Induced Neuropathic Nociception by Decoupling the Raphe Nucleus: A Functional Imaging Study in Rats. BIOLOGICAL PSYCHIATRY: COGNITIVE NEUROSCIENCE AND NEUROIMAGING 2020; 6:479-489. [PMID: 33622657 DOI: 10.1016/j.bpsc.2020.11.015] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 10/30/2020] [Accepted: 11/22/2020] [Indexed: 12/18/2022]
Abstract
BACKGROUND Efficacy of inhaled cannabis for treating pain is controversial. Effective treatment for chemotherapy-induced neuropathy represents an unmet medical need. We hypothesized that cannabis reduces neuropathic pain by reducing functional coupling in the raphe nuclei. METHODS We assessed the impact of inhalation of vaporized cannabis plant (containing 10.3% Δ9-tetrahydrocannabinol/0.05% cannabidiol) or placebo cannabis on brain resting-state blood oxygen level-dependent functional connectivity and pain behavior induced by paclitaxel in rats. Rats received paclitaxel to produce chemotherapy-induced peripheral neuropathy or its vehicle. Behavioral and imaging experiments were performed after neuropathy was established and stable. Images were registered to, and analyzed using, a 3D magnetic resonance imaging rat atlas providing site-specific data on more than 168 different brain areas. RESULTS Prior to vaporization, paclitaxel produced cold allodynia. Inhaled vaporized cannabis increased cold withdrawal latencies relative to prevaporization or placebo cannabis, consistent with Δ9-tetrahydrocannabinol-induced antinociception. In paclitaxel-treated rats, the midbrain serotonergic system, comprising the dorsal and median raphe, showed hyperconnectivity to cortical, brainstem, and hippocampal areas, consistent with nociceptive processing. Inhalation of vaporized cannabis uncoupled paclitaxel-induced hyperconnectivity patterns. No such changes in connectivity or cold responsiveness were observed following placebo cannabis vaporization. CONCLUSIONS Inhaled vaporized cannabis plant uncoupled brain resting-state connectivity in the raphe nuclei, normalizing paclitaxel-induced hyperconnectivity to levels observed in vehicle-treated rats. Inhaled vaporized cannabis produced antinociception in both paclitaxel- and vehicle-treated rats. Our study elucidates neural circuitry implicated in the therapeutic effects of Δ9-tetrahydrocannabinol and supports a role for functional imaging studies in animals in guiding indications for future clinical trials.
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Affiliation(s)
- Ilayda Alkislar
- Center for Translational Neuroimaging, Northeastern University, Boston, Massachusetts
| | - Alison R Miller
- Center for Translational Neuroimaging, Northeastern University, Boston, Massachusetts
| | - Andrea G Hohmann
- Psychological and Brain Sciences, Program in Neuroscience, and Gill Center for Biomolecular Science, Indiana University, Bloomington, Indiana
| | - Aymen H Sadaka
- Center for Translational Neuroimaging, Northeastern University, Boston, Massachusetts
| | - Xuezhu Cai
- Center for Translational Neuroimaging, Northeastern University, Boston, Massachusetts
| | - Praveen Kulkarni
- Center for Translational Neuroimaging, Northeastern University, Boston, Massachusetts
| | - Craig F Ferris
- Center for Translational Neuroimaging, Northeastern University, Boston, Massachusetts; Department of Psychology, Northeastern University, Boston, Massachusetts.
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Yeasmin F, Choi HW. Natural Salicylates and Their Roles in Human Health. Int J Mol Sci 2020; 21:ijms21239049. [PMID: 33260759 PMCID: PMC7731389 DOI: 10.3390/ijms21239049] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Revised: 11/25/2020] [Accepted: 11/26/2020] [Indexed: 01/04/2023] Open
Abstract
Salicylic acid (SA) is a plant hormone which plays a crucial role in the plant defense against various pathogens and abiotic stresses. Increasing reports suggest that this phenolic compound and its derivatives, collectively termed salicylates, not only regulate plant defense but also have beneficial effects on human health. Both natural and synthetic salicylates are known to have multiple targets in humans, thereby exhibiting various appreciating pharmacological roles, including anti-inflammatory, anticancer, neuroprotective, antidiabetic effects, and so on. The role of some salicylates, such as acetylsalicylic acid (aspirin), 5-aminosalicylic acid (mesalazine), and amorfrutins in human diseases has been well studied in vitro. However, their clinical significance in different diseases is largely unknown. Based on recent studies, five natural salicylates, including amorfrutin, ginkgolic acid, grifolic acid, tetrahydrocannabinolic acid, and cannabidiolic acid, showed potential roles in different challenging human diseases. This review summarizes together some of the recent information on multitarget regulatory activities of these natural salicylates and their pharmacological roles in human health.
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Mlost J, Bryk M, Starowicz K. Cannabidiol for Pain Treatment: Focus on Pharmacology and Mechanism of Action. Int J Mol Sci 2020; 21:ijms21228870. [PMID: 33238607 PMCID: PMC7700528 DOI: 10.3390/ijms21228870] [Citation(s) in RCA: 159] [Impact Index Per Article: 31.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Revised: 11/19/2020] [Accepted: 11/20/2020] [Indexed: 02/03/2023] Open
Abstract
Cannabis has a long history of medical use. Although there are many cannabinoids present in cannabis, Δ9tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) are the two components found in the highest concentrations. CBD itself does not produce typical behavioral cannabimimetic effects and was thought not to be responsible for psychotropic effects of cannabis. Numerous anecdotal findings testify to the therapeutic effects of CBD, which in some cases were further supported by research findings. However, data regarding CBD’s mechanism of action and therapeutic potential are abundant and omnifarious. Therefore, we review the basic research regarding molecular mechanism of CBD’s action with particular focus on its analgesic potential. Moreover, this article describes the detailed analgesic and anti-inflammatory effects of CBD in various models, including neuropathic pain, inflammatory pain, osteoarthritis and others. The dose and route of the administration-dependent effect of CBD, on the reduction in pain, hyperalgesia or allodynia, as well as the production of pro and anti-inflammatory cytokines, were described depending on the disease model. The clinical applications of CBD-containing drugs are also mentioned. The data presented herein unravel what is known about CBD’s pharmacodynamics and analgesic effects to provide the reader with current state-of-art knowledge regarding CBD’s action and future perspectives for research.
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Zagzoog A, Mohamed KA, Kim HJJ, Kim ED, Frank CS, Black T, Jadhav PD, Holbrook LA, Laprairie RB. In vitro and in vivo pharmacological activity of minor cannabinoids isolated from Cannabis sativa. Sci Rep 2020; 10:20405. [PMID: 33230154 PMCID: PMC7684313 DOI: 10.1038/s41598-020-77175-y] [Citation(s) in RCA: 114] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Accepted: 11/05/2020] [Indexed: 12/15/2022] Open
Abstract
The Cannabis sativa plant contains more than 120 cannabinoids. With the exceptions of ∆9-tetrahydrocannabinol (∆9-THC) and cannabidiol (CBD), comparatively little is known about the pharmacology of the less-abundant plant-derived (phyto) cannabinoids. The best-studied transducers of cannabinoid-dependent effects are type 1 and type 2 cannabinoid receptors (CB1R, CB2R). Partial agonism of CB1R by ∆9-THC is known to bring about the 'high' associated with Cannabis use, as well as the pain-, appetite-, and anxiety-modulating effects that are potentially therapeutic. CB2R activation by certain cannabinoids has been associated with anti-inflammatory activities. We assessed the activity of 8 phytocannabinoids at human CB1R, and CB2R in Chinese hamster ovary (CHO) cells stably expressing these receptors and in C57BL/6 mice in an attempt to better understand their pharmacodynamics. Specifically, ∆9-THC, ∆9-tetrahydrocannabinolic acid (∆9-THCa), ∆9-tetrahydrocannabivarin (THCV), CBD, cannabidiolic acid (CBDa), cannabidivarin (CBDV), cannabigerol (CBG), and cannabichromene (CBC) were evaluated. Compounds were assessed for their affinity to receptors, ability to inhibit cAMP accumulation, βarrestin2 recruitment, receptor selectivity, and ligand bias in cell culture; and cataleptic, hypothermic, anti-nociceptive, hypolocomotive, and anxiolytic effects in mice. Our data reveal partial agonist activity for many phytocannabinoids tested at CB1R and/or CB2R, as well as in vivo responses often associated with activation of CB1R. These data build on the growing body of literature showing cannabinoid receptor-dependent pharmacology for these less-abundant phytocannabinoids and are critical in understanding the complex and interactive pharmacology of Cannabis-derived molecules.
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Affiliation(s)
- Ayat Zagzoog
- College of Pharmacy and Nutrition, University of Saskatchewan, 3B36, Health Sciences Building, 107 Wiggins Road, Saskatoon, SK, S7N 2Z4, Canada
| | - Kawthar A Mohamed
- College of Pharmacy and Nutrition, University of Saskatchewan, 3B36, Health Sciences Building, 107 Wiggins Road, Saskatoon, SK, S7N 2Z4, Canada
| | - Hye Ji J Kim
- College of Pharmacy and Nutrition, University of Saskatchewan, 3B36, Health Sciences Building, 107 Wiggins Road, Saskatoon, SK, S7N 2Z4, Canada
| | - Eunhyun D Kim
- College of Pharmacy and Nutrition, University of Saskatchewan, 3B36, Health Sciences Building, 107 Wiggins Road, Saskatoon, SK, S7N 2Z4, Canada
| | - Connor S Frank
- College of Pharmacy and Nutrition, University of Saskatchewan, 3B36, Health Sciences Building, 107 Wiggins Road, Saskatoon, SK, S7N 2Z4, Canada
| | - Tallan Black
- College of Pharmacy and Nutrition, University of Saskatchewan, 3B36, Health Sciences Building, 107 Wiggins Road, Saskatoon, SK, S7N 2Z4, Canada
| | | | | | - Robert B Laprairie
- College of Pharmacy and Nutrition, University of Saskatchewan, 3B36, Health Sciences Building, 107 Wiggins Road, Saskatoon, SK, S7N 2Z4, Canada. .,Department of Pharmacology, College of Medicine, Dalhousie University, Halifax, NS, Canada.
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Stone NL, Murphy AJ, England TJ, O'Sullivan SE. A systematic review of minor phytocannabinoids with promising neuroprotective potential. Br J Pharmacol 2020; 177:4330-4352. [PMID: 32608035 PMCID: PMC7484504 DOI: 10.1111/bph.15185] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 06/16/2020] [Accepted: 06/23/2020] [Indexed: 12/18/2022] Open
Abstract
Embase and PubMed were systematically searched for articles addressing the neuroprotective properties of phytocannabinoids, apart from cannabidiol and Δ9 -tetrahydrocannabinol, including Δ9 -tetrahydrocannabinolic acid, Δ9 -tetrahydrocannabivarin, cannabidiolic acid, cannabidivarin, cannabichromene, cannabichromenic acid, cannabichromevarin, cannabigerol, cannabigerolic acid, cannabigerivarin, cannabigerovarinic acid, cannabichromevarinic acid, cannabidivarinic acid, and cannabinol. Out of 2,341 studies, 31 articles met inclusion criteria. Cannabigerol (range 5 to 20 mg·kg-1 ) and cannabidivarin (range 0.2 to 400 mg·kg-1 ) displayed efficacy in models of Huntington's disease and epilepsy. Cannabichromene (10-75 mg·kg-1 ), Δ9 -tetrahydrocannabinolic acid (20 mg·kg-1 ), and tetrahydrocannabivarin (range 0.025-2.5 mg·kg-1 ) showed promise in models of seizure and hypomobility, Huntington's and Parkinson's disease. Limited mechanistic data showed cannabigerol, its derivatives VCE.003 and VCE.003.2, and Δ9 -tetrahydrocannabinolic acid mediated some of their effects through PPAR-γ, but no other receptors were probed. Further studies with these phytocannabinoids, and their combinations, are warranted across a range of neurodegenerative disorders.
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Affiliation(s)
- Nicole L. Stone
- Division of Medical Sciences and Graduate Entry Medicine, School of MedicineUniversity of Nottingham, Royal Derby HospitalDerbyUK
| | - Alexandra J. Murphy
- Division of Medical Sciences and Graduate Entry Medicine, School of MedicineUniversity of Nottingham, Royal Derby HospitalDerbyUK
| | - Timothy J. England
- Division of Medical Sciences and Graduate Entry Medicine, School of MedicineUniversity of Nottingham, Royal Derby HospitalDerbyUK
| | - Saoirse E. O'Sullivan
- Division of Medical Sciences and Graduate Entry Medicine, School of MedicineUniversity of Nottingham, Royal Derby HospitalDerbyUK
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