“Contact hypersensitivity (CHS) is an established animal model for allergic contact dermatitis. Dendritic cells (DCs) play an important role in the sensitization phase of CHS by initiating T cell responses to topically applied haptens. The cannabinoid receptors 1 (CB1) and 2 (CB2) modulate DC functions and inflammatory skin responses, but their influence on the capacity of haptenized DCs to induce CHS is still unknown. We found lower CHS responses to 2,4-dinitro-1-fluorobenzene (DNFB) in wild type (WT) mice after adoptive transfer of haptenized Cnr2-/- and Cnr1-/-/Cnr2-/- bone marrow (BM) DCs as compared to transfer of WT DCs. In contrast, induction of CHS was not affected in WT recipients after transfer of Cnr1-/- DCs. In vitro stimulated Cnr2-/- DCs showed lower CCR7 and CXCR4 expression when compared to WT cells, while in vitro migration towards the chemokine ligands was not affected by CB2. Upregulation of MHC class II and co-stimulatory molecules was also reduced in Cnr2-/- DCs. This study demonstrates that CB2 modulates the maturation phenotype of DCs but not their chemotactic capacities in vitro. These findings and the fact that CHS responses mediated by Cnr2-/- DCs are reduced suggest that CB2 is a promising target for the treatment of inflammatory skin conditions.”
Nose-to-brain Delivery of Natural Compounds for the Treatment of Central Nervous System Disorders.
“Several natural compounds have demonstrated potential for the treatment of central nervous system disorders such as ischemic cerebrovascular disease, glioblastoma, neuropathic pain, neurodegenerative diseases, multiple sclerosis and migraine.
This is due to their well-known antioxidant, anti-inflammatory, neuroprotective, anti-tumor, anti-ischemic and analgesic properties. Nevertheless, many of these molecules have poor aqueous solubility, low bioavailability and extensive gastrointestinal and/or hepatic first-pass metabolism, leading to a quick elimination as well as low serum and tissue concentrations.
Thus, the intranasal route emerged as a viable alternative to oral or parenteral administration, by enabling a direct transport into the brain through the olfactory and trigeminal nerves. With this approach, the blood-brain barrier is circumvented and peripheral exposure is reduced, thereby minimizing possible adverse effects.
OBJECTIVE:
Herein, brain-targeting strategies for the nose-to-brain delivery of natural compounds, including flavonoids, cannabinoids, essential oils and terpenes, will be reviewed and discussed. Brain and plasma pharmacokinetics of these molecules will be analyzed and related to their physicochemical characteristics and formulation properties.
CONCLUSION:
Natural compounds constitute relevant alternatives for the treatment of brain diseases but often require loading into nanocarrier systems to reach the central nervous system in sufficient concentrations. Future challenges lie in a deeper characterization of their therapeutic mechanisms and in the development of effective, safe and brain-targeted delivery systems for their intranasal administration.”
Challenges and Opportunities in Preclinical Research of Synthetic Cannabinoids for Pain Therapy.
“Cannabis has been used in pain management since 2900 BC.
In the 20th century, synthetic cannabinoids began to emerge, thus opening the way for improved efficacy. The search for new forms of synthetic cannabinoids continues and, as such, the aim of this review is to provide a comprehensive tool for the research and development of this promising class of drugs.
Methods for the in vitro assessment of cytotoxic, mutagenic or developmental effects are presented, followed by the main in vivo pain models used in cannabis research and the results yielded by different types of administration (systemic versus intrathecal versus inhalation). Animal models designed for assessing side-effects and long-term uses are also discussed.
In the second part of this review, pharmacokinetic and pharmacodynamic studies of synthetic cannabinoid biodistribution, together with liquid chromatography-mass spectrometric identification of synthetic cannabinoids in biological fluids from rodents to humans are presented. Last, but not least, different strategies for improving the solubility and physicochemical stability of synthetic cannabinoids and their potential impact on pain management are discussed.
In conclusion, synthetic cannabinoids are one of the most promising classes of drugs in pain medicine, and preclinical research should focus on identifying new and improved alternatives for a better clinical and preclinical outcome.”
Cannabidiol (CBD) for Treatment of Neurofibromatosis-related Pain and Concomitant Mood Disorder: A Case Report.
“Neurofibromatosis type 1 (NF1) is a common genetic disorder. Pain is a major symptom of this disease which can be secondary to the development of plexiform and subcutaneous neurofibromas, musculoskeletal symptoms (such as scoliosis and pseudoarthrosis), and headaches. Visible neurofibromas add significant psychosocial distress for NF1 patients. Along with the chronic pain, psychosocial distress contributes to associated mood disorders, such as depression and anxiety.
Cannabis has been the focus of many studies for treating multiple conditions, including epilepsy, multiple sclerosis, Parkinsonism disease, and many chronic pain conditions. Cannabidiol (CBD) is the major non-psychotropic component of cannabis. CBD has shown anti-inflammatory and analgesic properties, as well as having mood stabilizer and anxiolytic effects.
In this report, we present the use of cannabidiol (CBD) for the management of chronic pain and concomitant mood disorder in an NF1 patient.”
Use of cannabinoids in cancer patients: A Society of Gynecologic Oncology (SGO) clinical practice statement.
“Tetrahydrocannabinol (THC), cannabidiol (CBD) and cannabinol (CBN) affect the human endocannabinoid system.
Cannabinoids reduce chemotherapy induced nausea or vomiting (CINV) and neuropathic pain.
Each state has its own regulations for medical and recreational cannabis use.
Effects of cannabinoids on chemotherapy, immunotherapy, and tumor growth remain under investigation.
Providers should focus indications, alternatives, risks and benefits of medical cannabis use to make appropriate referrals.”
https://www.ncbi.nlm.nih.gov/pubmed/31932107
https://www.gynecologiconcology-online.net/article/S0090-8258(19)31805-0/fulltext
Nightmares and the Cannabinoids.
“The cannabinoids, δ9 tetrahydrocannabinol and its analogue, nabilone, have been found to reliably attenuate the intensity and frequency of post-traumatic nightmares.
This essay examines how a traumatic event is captured in the mind after just a single exposure and repeatedly replicated during the nights that follow.
The adaptive neurophysiological, endocrine and inflammatory changes that are triggered by the trauma and that alter personality and behavior are surveyed. These adaptive changes, once established, can be difficult to reverse. But cannabinoids, uniquely, have been shown to interfere with all of these post-traumatic somatic adaptations.
While cannabinoids can suppress nightmares and other symptoms of the post-traumatic stress disorder, they are not a cure. There may be no cure.
The cannabinoids may best be employed, alone, but more likely in conjunction with other agents, in the immediate aftermath of a trauma to mitigate or even abort the metabolic changes which are set in motion by the trauma and which may permanently alter the reactivity of the nervous system. Steps in this direction have already been taken.”
Activation of cannabinoid receptor type 2 reduces lung ischemia reperfusion injury through PI3K/Akt pathway.
“Cannabinoid receptor-2 activation plays a protective role against ischemic reperfusion injury (IRI) in various organs, and exerts a protective effect against paraquat-induced acute lung injury, while the role of CB2 in lung IRI remains unclear.
Hence, the present study was designed to explore the role of CB2 in lung IRI, and whether the PI3K pathway was involved.
The study suggested that activation of CB2 receptor plays a protective role against IR-induced lung injury through reducing inflammation in mice.
The PI3K/Akt pathway might be involved in the protective effect of CB2 receptors in lung IRI.”
Involvement of endocannabinoid system, inflammation and apoptosis in diabetes induced liver injury: Role of 5-HT3 receptor antagonist.
“Confident relationships between diabetes and liver damage have previously been established.
This study was designed to evaluate hepaticinflammation, apoptosis, and endocannabinoid system alterations in diabetes with or without tropisetron treatment.
These findings strongly support the idea that diabetes-induced liver abnormality is mediated by inflammatory reactions, apoptosis, and endocannabinoid system, and that these effects can be alleviated by using tropisetron as an antioxidant and anti-inflammatory agent.”
https://www.ncbi.nlm.nih.gov/pubmed/31926479
https://www.sciencedirect.com/science/article/pii/S1567576919322684?via%3Dihub
Disease-modifying effects of natural Δ9-tetrahydrocannabinol in endometriosis-associated pain.
“Endometriosis is a chronic painful disease highly prevalent in women that is defined by growth of endometrial tissue outside the uterine cavity and lacks adequate treatment.
Medical use of cannabis derivatives is a current hot topic and it is unknown whether phytocannabinoids may modify endometriosis symptoms and development.
Here we evaluate the effects of repeated exposure to Δ9-tetrahydrocannabinol (THC) in a mouse model of surgically-induced endometriosis.
In this model, female mice develop mechanical hypersensitivity in the caudal abdomen, mild anxiety-like behavior and substantial memory deficits associated with the presence of extrauterine endometrial cysts.
Interestingly, daily treatments with THC (2 mg/kg) alleviate mechanical hypersensitivity and pain unpleasantness, modify uterine innervation and restore cognitive function without altering the anxiogenic phenotype. Strikingly, THC also inhibits the development of endometrial cysts.
These data highlight the interest of scheduled clinical trials designed to investigate possible benefits of THC for women with endometriosis.”
The role of cannabinoids in epilepsy treatment: a critical review of efficacy results from clinical trials.
“CBD was shown to have anti-seizure activity based on in vitro and in vivo models.
However, several reports of small series or case reports of the use of cannabis extracts in epilepsy yielded contradictory results and the efficacy of cannabis use in patients with epilepsy have also been inconclusive.
In 2013, the first Phase 1 trial for a purified form of CBD (Epidiolex/Epidyolex; >99% CBD), developed by GW Pharma, showed some efficacy signals and subsequently, a comprehensive program on the efficacy and tolerability of this compound for the treatment of drug-resistant epilepsies was initiated.
Results of these trials led to the FDA and EMA approval respectively in 2018 and 2019 for the treatment of seizures associated with two rare epilepsies: Lennox-Gastaut syndrome (LGS) or Dravet syndrome (DS) in patients two years of age and older.
Thus, CBD became the first FDA-approved purified drug substance derived from cannabis and also the first FDA-approved drug for the treatment of seizures in DS.
We detail the clinical studies using purified CBD (Epidiolex/Epidyolex), including the first open interventional exploratory study and Randomized Control Ttrials for DS and LGS.”