Phytocannabinoids in Neurological Diseases: Could They Restore a Physiological GABAergic Transmission?

Posted on January 29, 2020 by David

“γ-Aminobutyric acid type A receptors (GABA_ARs) are the main inhibitory mediators in the central nervous system (CNS). GABA_ARs are pentameric ligand gated ion channels, and the main subunit composition is usually 2α2βγ, with various isotypes assembled within a set of 19 different subunits. The inhibitory function is mediated by chloride ion movement across the GABA_ARs, activated by synaptic GABA release, reducing neuronal excitability in the adult CNS. Several studies highlighted the importance of GABA-mediated transmission during neuro-development, and its involvement in different neurological and neurodevelopmental diseases, from anxiety to epilepsy. However, while it is well known how different classes of drugs are able to modulate the GABA_ARs function (benzodiazepines, barbiturates, neurosteroids, alcohol), up to now little is known about GABA_ARs and cannabinoids interaction in the CNS. Endocannabinoids and phytocannabinoids are lately emerging as a new class of promising drugs for a wide range of neurological conditions, but their safety as medication, and their mechanisms of action are still to be fully elucidated. In this review, we will focus our attention on two of the most promising molecules (Δ9-tetrahydrocannabinol; Δ9-THC and cannabidiol; CBD) of this new class of drugs and their possible mechanism of action on GABA_ARs.”

https://www.ncbi.nlm.nih.gov/pubmed/31979108

https://www.mdpi.com/1422-0067/21/3/723

Allosteric Cannabinoid Receptor 1 (CB1) Ligands Reduce Ocular Pain and Inflammation.

Posted on January 25, 2020 by David

“Cannabinoid receptor 1 (CB1) activation has been reported to reduce transient receptor potential cation channel subfamily V member 1 (TRPV1)-induced inflammatory responses and is anti-nociceptive and anti-inflammatory in corneal injury.

We examined whether allosteric ligands, can modulate CB1 signaling to reduce pain and inflammation in corneal hyperalgesia.

Corneal hyperalgesia was generated by chemical cauterization of cornea in wildtype and CB2 knockout (CB2^-/-) mice. The novel racemic CB1 allosteric ligand GAT211 and its enantiomers GAT228 and GAT229 were examined alone or in combination with the orthosteric CB1 agonist Δ⁸-tetrahydrocannabinol (Δ⁸-THC). Pain responses were assessed following capsaicin (1 µM) stimulation of injured corneas at 6 h post-cauterization. Corneal neutrophil infiltration was also analyzed. GAT228, but not GAT229 or GAT211, reduced pain scores in response to capsaicin stimulation.

Combination treatments of 0.5% GAT229 or 1% GAT211 with subthreshold Δ⁸-THC (0.4%) significantly reduced pain scores following capsaicin stimulation. The anti-nociceptive effects of both GAT229 and GAT228 were blocked with CB1 antagonist AM251, but remained unaffected in CB2^-/- mice. Two percent GAT228, or the combination of 0.2% Δ⁸-THC with 0.5% GAT229 also significantly reduced corneal inflammation.

CB1 allosteric ligands could offer a novel approach for treating corneal pain and inflammation.”

https://www.ncbi.nlm.nih.gov/pubmed/31968549

https://www.mdpi.com/1420-3049/25/2/417

The effect of orally administered dronabinol on optic nerve head blood flow in healthy subjects- a randomized clinical trial.

Posted on January 25, 2020 by David

Publication cover image “It has been hypothesized that besides its intraocular pressure (IOP) lowering potential, tetrahydrocannabinol (THC) may also improve ocular hemodynamics.

The aim of the present study was to investigate whether single oral administration of dronabinol, a synthetic THC, alters optic nerve head blood flow (ONHBF) and its regulation in healthy subjects.

The study was carried out in a randomized, placebo-controlled, double-masked, two-way crossover design in twenty-four healthy subjects. For each study participant, two study days were scheduled, on which they either received capsules containing 5mg dronabinol or placebo. ONHBF was measured with laser Doppler flowmetry at rest and while the study participants performed isometric exercise for six minutes to increase mean arterial blood pressure (MAP). This was repeated one hour after drug intake. Ocular perfusion pressure (OPP) was calculated as 2/3MAP-IOP.

Dronabinol was well tolerated and no cannabinoid-related psychoactive effects were reported.

Neither administration of dronabinol nor placebo had an effect on IOP, MAP or OPP. In contrast, dronabinol significantly increased ONHBF at rest by 9.5±8.1% whereas placebo did not show a change in ONHBF (0.3±7.4% vs. baseline, p<0.001 between study days). Dronabinol did not alter the autoregulatory response of ONHBF to isometric exercise.

In conclusion, the present data indicate that low dose dronabinol increases ONHBF in healthy subjects without affecting IOP, OPP or inducing psychoactive side effects. In addition, dronabinol does not alter the autoregulatory response of ONHBF to an experimental increase in OPP. Further studies are needed to investigate whether this effect can also be observed in glaucoma patients.”

https://www.ncbi.nlm.nih.gov/pubmed/31977076

https://ascpt.onlinelibrary.wiley.com/doi/abs/10.1002/cpt.1797

A Review on Studies of Marijuana for Alzheimer’s Disease – Focusing on CBD, THC.

Posted on January 25, 2020 by David

book “This study was to discuss the research trend of dementia treatment using cannabis for the purpose of providing the basis of cannabis use for medical purposes in the future.

RESULTS:

These results implied that the CBD components of cannabis might be useful to treat and prevent AD because CBD components could suppress the main causal factors of AD.

Moreover, it was suggested that using CBD and THC together could be more useful than using CBD or THC alone.

CONCLUSION:

We hope that there will be a solid foundation to use cannabis for medical use by continuously evaluating the possibility of using cannabis for clinical purposes as a dementia treatment substance and cannabis can be used as a positive tool.”

https://www.ncbi.nlm.nih.gov/pubmed/31970019

“The ideal treatment for Alzheimer’s disease (AD) should be able to modulate the disease through multiple mechanisms rather than targeting a single dysregulated pathway.” http://www.ncbi.nlm.nih.gov/pubmed/25147120

“THC could be a potential therapeutic treatment option for Alzheimer’s disease through multiple functions and pathways.” http://www.ncbi.nlm.nih.gov/pubmed/25024327

“CBD treatment would be in line with preventative, multimodal drug strategies targeting a combination of pathological symptoms, which might be ideal for AD #therapy.” http://www.ncbi.nlm.nih.gov/pubmed/27471947

“Combination of THC and CBD exhibits a better therapeutic profile than each cannabis component alone and support the consideration of a cannabis-based medicine as potential therapy against AD.” http://www.ncbi.nlm.nih.gov/pubmed/25125475

http://www.thctotalhealthcare.com/category/alzheimers-disease-ad/

Cannabinoids CB2 Receptors, One New Promising Drug Target for Chronic and Degenerative Pain Conditions in Equine Veterinary Patients.

Posted on January 21, 2020 by David

Journal of Equine Veterinary Science “Osteoarticular equine disease is a common cause of malady; in general, its therapy is supported on steroids and nonsteroidal anti-inflammatories. Nevertheless, many side effects may develop when these drugs are administered. Nowadays, the use of new alternatives for this pathology attention is demanded; in that sense, cannabinoid CB2 agonists may represent a novel alternative.

Cannabinoid belongs to a group of molecules known by their psychoactive properties; they are synthetized by the Cannabis sativa plant, better known as marijuana.

The aim of this study was to contribute to understand the pharmacology of cannabinoid CB2 receptors and its potential utilization on equine veterinary patients with a chronic degenerative painful condition. In animals, two main receptors for cannabinoids are recognized, the cannabinoid receptor type 1 and the cannabinoid receptor type 2. Once they are activated, both receptors exert a wide range of physiological responses, as nociception modulation.

Recently, it has been proposed the use of synthetic cannabinoid type 2 receptor agonists; those receptors looks to confer antinociceptive properties but without the undesired psychoactive side effects; for that reason, veterinary patients, whit chronical degenerative diseases as osteoarthritis may alleviate one of the most common symptom, the pain, which in some cases for several reasons, as patient individualities, or side effects produced for more conventional treatments cannot be attended in the best way.”

https://www.ncbi.nlm.nih.gov/pubmed/31952645

https://www.sciencedirect.com/science/article/abs/pii/S073708061930629X?via%3Dihub

Source of cannabinoids: what is available, what is used, and where does it come from?

Posted on January 18, 2020 by David

“Cannabis sativa L. is an ancient medicinal plant wherefrom over 120 cannabinoids are extracted. In the past two decades, there has been increasing interest in the therapeutic potential of cannabis-based treatments for neurological disorders such as epilepsy, and there is now evidence for the medical use of cannabis and its effectiveness for a wide range of diseases.

Cannabinoid treatments for pain and spasticity in patients with multiple sclerosis (Nabiximols) have been approved in several countries. Cannabidiol (CBD), in contrast to tetra-hydro-cannabidiol (THC), is not a controlled substance in the European Union, and over the years there has been increasing use of CBD-enriched extracts and pure CBD for seizure disorders, particularly in children. No analytical controls are mandatory for CBD-based products and a pronounced variability in CBD concentrations in commercialized CBD oil preparations has been identified.

Randomized controlled trials of plant-derived CBD for treatment of Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS) have provided evidence of anti-seizure effects, and in June 2018, CBD was approved by the Food and Drug Administration as an add-on antiepileptic drug for patients two years of age and older with LGS or DS. Medical cannabis, with various ratios of CBD and THC and in different galenic preparations, is licensed in many European countries for several indications, and in July 2019, the European Medicines Agency also granted marketing authorisation for CBD in association with clobazam, for the treatment of seizures associated with LGS or DS.

The purpose of this article is to review the availability of cannabis-based products and cannabinoid-based medicines, together with current regulations regarding indications in Europe (as of July 2019). The lack of approval by the central agencies, as well as social and political influences, have led to significant variation in usage between countries.”

https://www.ncbi.nlm.nih.gov/pubmed/31941643

https://www.jle.com/fr/revues/epd/e-docs/source_of_cannabinoids_what_is_available_what_is_used_and_where_does_it_come_from__316043/article.phtml

The Impact of Medical Cannabis on Intermittent and Chronic Opioid Users with Back Pain: How Cannabis Diminished Prescription Opioid Usage

Posted on January 17, 2020 by David

View details for Cannabis and Cannabinoid Research cover image “To determine if cannabis may be used as an alternative or adjunct treatment for intermittent and chronic prescription opioid users.

Design: Retrospective cohort study.

Setting: A single-center cannabis medical practice site in California.

Patients: A total of 180 patients who had a chief complaint of low back pain were identified (International Classification of Diseases, 10th Revision, code M54.5). Sixty-one patients who used prescription opioids were analyzed.

Interventions: Cannabis recommendations were provided to patients as a way to mitigate their low back pain.

Outcome Measures: Number of patients who stopped opioids and change in morphine equivalents.

Results: There were no between-group differences based on demographic, experiential, or attitudinal variables. We found that 50.8% were able to stop all opioid usage, which took a median of 6.4 years (IQR=1.75–11 years) after excluding two patients who transitioned off opioids by utilizing opioid agonists. For those 29 patients (47.5%) who did not stop opioids, 9 (31%) were able to reduce opioid use, 3 (10%) held the same baseline, and 17 (59%) increased their usage. Forty-eight percent of patients subjectively felt like cannabis helped them mitigate their opioid intake but this sentiment did not predict who actually stopped opioid usage. There were no variables that predicted who stopped opioids, except that those who used higher doses of cannabis were more likely to stop, which suggests that some patients might be able to stop opioids by using cannabis, particularly those who are dosed at higher levels.

Conclusions: In this long-term observational study, cannabis use worked as an alternative to prescription opioids in just over half of patients with low back pain and as an adjunct to diminish use in some chronic opioid users.”

https://www.liebertpub.com/doi/abs/10.1089/can.2019.0039

Cannabinoid Receptor 2 Modulates Maturation of Dendritic Cells and Their Capacity to Induce Hapten-Induced Contact Hypersensitivity.

Posted on January 17, 2020 by David

“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.”

https://www.ncbi.nlm.nih.gov/pubmed/31940843

https://www.mdpi.com/1422-0067/21/2/475

Challenges and Opportunities in Preclinical Research of Synthetic Cannabinoids for Pain Therapy.

Posted on January 16, 2020 by David

“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.”

https://www.ncbi.nlm.nih.gov/pubmed/31936616

https://www.mdpi.com/1010-660X/56/1/24