Effects of Chronic Cannabidiol Treatment in the Rat Chronic Unpredictable Mild Stress Model of Depression

biomolecules-logo“Several neuropharmacological actions of cannabidiol (CBD) due to the modulation of the endocannabinoid system as well as direct serotonergic and gamma-aminobutyric acidergic actions have recently been identified.

The current study aimed to reveal the effect of a long-term CBD treatment in the chronic unpredictable mild stress (CUMS) model of depression.

Adult male Wistar rats (n = 24) were exposed to various stressors on a daily basis in order to induce anhedonia and anxiety-like behaviors. CBD (10 mg/kg body weight) was administered by daily intraperitoneal injections for 28 days (n = 12). The effects of the treatment were assessed on body weight, sucrose preference, and exploratory and anxiety-related behavior in the open field (OF) and elevated plus maze (EPM) tests. Hair corticosterone was also assayed by liquid chromatography-mass spectrometry.

At the end of the experiment, CBD-treated rats showed a higher rate of body weight gain (5.94% vs. 0.67%) and sucrose preference compared to controls. A significant increase in vertical exploration and a trend of increase in distance traveled in the OF test were observed in the CBD-treated group compared to the vehicle-treated group. The EPM test did not reveal any differences between the groups. Hair corticosterone levels increased in the CBD-treated group, while they decreased in controls compared to baseline (+36.01% vs. -45.91%). In conclusion, CBD exerted a prohedonic effect in rats subjected to CUMS, demonstrated by the increased sucrose preference after three weeks of treatment.

The reversal of the effect of CUMS on hair corticosterone concentrations might also point toward an anxiolytic or antidepressant-like effect of CBD, but this needs further confirmation.”

https://pubmed.ncbi.nlm.nih.gov/32455953/

https://www.mdpi.com/2218-273X/10/5/801

Does Cannabidiol Have Antiseizure Activity Independent of Its Interactions With Clobazam? An Appraisal of the Evidence From Randomized Controlled Trials

 Epilepsia“Four pivotal randomized placebo-controlled trials have demonstrated that adjunctive therapy with cannabidiol (CBD) improves seizure control in patients with Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS).

Between 47% and 68% of patients allocated to CBD treatment in these trials were receiving clobazam (CLB), which shows complex interactions with CBD resulting, in particular, in a 3.4- to 5-fold increase in plasma concentration of the active metabolite norclobazam. This raises concern as to the role played by these interactions in determining the reduction in seizure frequency in CBD-treated patients, and the question of whether CBD per se has clinically evident antiseizure effects.

We appraised available evidence on the clinical consequences of the CBD-CLB interaction, focusing on subgroup analyses of seizure outcomes in patients on and off CLB comedication in the pivotal CBD trials, as provided by the European Medicines Agency Public Assessment Report.

Evaluation of the results of individual trials clearly showed that improvement in seizure control over placebo was greater when CBD was added on to CLB than when it was added on to other medications. However, seizure control was also improved in patients off CLB, and despite the small sample size the difference vs placebo was statistically significant for the 10 mg/kg/d dose in one of the two LGS trials.

Stronger evidence for an antiseizure effect of CBD independent of an interaction with CLB emerges from meta-analyses of seizure outcomes in the pooled population of LGS and DS patients not receiving CLB comedication.

Although these results need to be interpreted taking into account methodological limitations, they provide the best clinical evidence to date that CBD exerts therapeutic effects in patients with epilepsy that are independent of its interaction with CLB. Greater antiseizure effects, and a greater burden of adverse effects, are observed when CBD is combined with CLB.”

https://pubmed.ncbi.nlm.nih.gov/32452568/

https://onlinelibrary.wiley.com/doi/abs/10.1111/epi.16542

Post Marketing Safety of Plus CBD™ Products, a Full Spectrum Hemp Extract: A 2-Year Experience

 Publication Cover“The market for products featuring hemp extracts is large and growing larger. However, safety concerns have been raised by medical and regulatory agencies. Post marketing surveillance of full spectrum hemp extract (FSHE) products manufactured and distributed by CV Sciences (CVSI) and traded under the brand PlusCBD™ was conducted over a 2-year period (2018-2019). The safety of these products was assessed by analyzing adverse events reports.

From a total of approximately five million product units sold during the 2-year period, 1,429 (0.03%) adverse events (AE) were reported in 1,151 unique customers. Of those, only two were classified as serious AEs. For orally ingested products, the most common types of AEs reported were gastrointestinal (e.g. abdominal discomfort), while for topically applied products, the most reports mentioned dermatological symptoms (e.g. rashes). There has been no evidence of liver toxicity associated with CVSI products.

Based on this longitudinal dataset, the products manufactured using CVSI’s proprietary processes are safe and well tolerated at the recommended doses.”

https://pubmed.ncbi.nlm.nih.gov/32449632/

https://www.tandfonline.com/doi/abs/10.1080/19390211.2020.1767255?journalCode=ijds20

Nabiximols Plus Robotic Assisted Gait Training in Improving Motor Performances in People With Multiple Sclerosis

szklerózis multiplex Archives | Magyar Orvosi Kannabisz Egyesület“Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system, affecting ambulation even in people with only mild neurological signs. Patients with MS frequently experience spasticity, which contributes significantly to impair their motor functions, including ambulation, owing to muscle stiffness, spasms, and pain.

Objectives: To clarify the role of delta-9-tetrahydrocannabinol(THC):cannabidiol(CBD) oromucosal spray, coupled to robot-aided gait training (RAGT) using the Lokomat©Pro to improve functional ambulation in patients with MS.

Methods: We compared 20 patients with MS, who were treated with THC:CBD oromucosal spray in add-on to the ongoing oral antispastic therapy (OAT) (group A), with 20 individuals with MS (matched for clinical-demographic characteristics) who were treated only with OAT (group B). Both the groups underwent RAGT using the Lokomat-Pro (three 45-minute sessions per week). Our primary outcome measures were the Functional Independence Measure (FIM) and the 10 meters walking test (10MWT). As secondary outcome measures we evaluated the brain cortical excitability by using Transcranial Magnetic Stimulation. Both parameters were taken before and after the end of the RAGT.

Results: FIM improved in group A more than in group B (p<0.001). Moreover, 10MWT decreased in group A more than in group B (p<0.001). These clinical findings were paralleled by a more evident reshape of intracortical excitability in both upper and lower limbs, as suggested by motor evoked potential amplitude increase (p<0.001), intracortical inhibition strengthening (p<0.001), and intracortical facilitation decrease (p=0.01) in group A as compared to group B.

Conclusions: Our results suggest that the combined THC:CBD-RAGT approach could be useful in improving gait performance in patients with MS.”

https://pubmed.ncbi.nlm.nih.gov/32447249/

“The coupled therapy is preliminarily demonstrated as safe and efficacious.”

https://www.msard-journal.com/article/S2211-0348(20)30253-4/pdf

Antioxidant and Neuroprotective Effects Induced by Cannabidiol and Cannabigerol in Rat CTX-TNA2 Astrocytes and Isolated Cortexes

ijms-logo“Cannabidiol (CBD) and cannabigerol (CBG) are Cannabis sativa terpenophenols.

Although CBD’s effectiveness against neurological diseases has already been demonstrated, nothing is known about CBG. Therefore, a comparison of the effects of these compounds was performed in two experimental models mimicking the oxidative stress and neurotoxicity occurring in neurological diseases.

Rat astrocytes were exposed to hydrogen peroxide and cell viability, reactive oxygen species production and apoptosis occurrence were investigated. Cortexes were exposed to K+ 60 mM depolarizing stimulus and serotonin (5-HT) turnover, 3-hydroxykinurenine and kynurenic acid levels were measured. A proteomic analysis and bioinformatics and docking studies were performed.

Both compounds exerted antioxidant effects in astrocytes and restored the cortex level of 5-HT depleted by neurotoxic stimuli, whereas sole CBD restored the basal levels of 3-hydroxykinurenine and kynurenic acid. CBG was less effective than CBD in restoring the levels of proteins involved in neurotransmitter exocytosis. Docking analyses predicted the inhibitory effects of these compounds towards the neurokinin B receptor.

Conclusion: The results in the in vitro system suggest brain non-neuronal cells as a target in the treatment of oxidative conditions, whereas findings in the ex vivo system and docking analyses imply the potential roles of CBD and CBG as neuroprotective agents.”

https://pubmed.ncbi.nlm.nih.gov/32443623/

https://www.mdpi.com/1422-0067/21/10/3575

CBD Suppression of EAE Is Correlated With Early Inhibition of Splenic IFN-γ + CD8+ T Cells and Modest Inhibition of Neuroinflammation

SpringerLink “In this study cannabidiol (CBD) was administered orally to determine its effects and mechanisms in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS). We hypothesized that 75 mg/kg of oral CBD given for 5 days after initiation of disease would reduce EAE severity through suppression of either the early peripheral immune or late neuroimmune response.

EAE was induced in C57BL/6 mice at two different magnitudes, and peripheral inflammatory and neuroinflammatory responses were measured at days 3, 10, and 18. Th1, Th17, Tc1, Tc17, Tregs, and myeloid derived suppressor cells (MDSC) were identified from the lymph nodes and spleens of each mouse to determine if CBD altered the suppressor cell or inflammatory cell populations in secondary lymphoid tissues. Additionally, neuroinflammation was identified in brain and spinal cord tissues using various immunohistochemical techniques and flow cytometry.

Early treatment of EAE with oral CBD reduced clinical disease at the day 18 timepoint which correlated with a significant decrease in the percentage of MOG35-55 specific IFN-γ producing CD8+ T cells in the spleen at day 10. Analysis of both T cell infiltration and lesion size within the spinal cord also showed a moderate reduction in neuroinflammation within the central nervous system (CNS).

These results provide evidence that oral CBD suppressed the peripheral immune response that precedes neuroinflammation; however, analysis of the neuroinflammatory endpoints also suggest that the modest reduction in neuroinflammation was only partially responsible for CBD’s neuroprotective capability. Graphical Abstract CBD was administered orally for the first 5 days following initiation of EAE. CBD attenuated clinical disease, and we found that CBD suppressed IFN-γ producing CD8+ T cells in the spleen at day 10. There was also modest suppression of neuroinflammation.

Together these data demonstrate that early, oral administration of CBD protected mice from disease, but the modest effects on neuroinflammation suggest other mechanisms participate in CBD’s neuroprotective effect in EAE.”

https://pubmed.ncbi.nlm.nih.gov/32440886/

https://link.springer.com/article/10.1007%2Fs11481-020-09917-8

Cannabidiol Prevents the Expression of the Locomotor Sensitization and the Metabolic Changes in the Nucleus Accumbens and Prefrontal Cortex Elicited by the Combined Administration of Cocaine and Caffeine in Rats

 SpringerLink“In the last years, clinical and preclinical researchers have increased their interest in non-psychotomimetic cannabinoids, like cannabidiol (CBD), as a strategy for treating psychostimulant use disorders. However, there are discrepancies in the pharmacological effects and brain targets of CBD.

We evaluated if CBD was able to prevent the locomotor sensitization elicited by cocaine and caffeine co-administration. The effect of CBD on putative alterations in the metabolic activity of the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc), and its respective subregions (cingulated, prelimbic, and infralimbic cortices, and NAc core and shell) associated to the behavioral response, was also investigated.

Rats were intraperitoneally and repeatedly treated with CBD (20 mg/kg) or its vehicle, followed by the combination of cocaine and caffeine (Coc+Caf; 5 mg/kg and 2.5 mg/kg, respectively) or saline for 3 days. After 5 days of withdrawal, all animals were challenged with Coc+Caf (day 9). Locomotor activity was automatically recorded and analyzed by a video-tracking software.

The metabolic activity was determined by measuring cytochrome oxidase-I (CO-I) staining. Locomotion was significantly and similarly increased both in Veh-Coc+Caf- and CBD-Coc+Caf-treated animals during the pretreatment period (3 days); however, on day 9, the expression of the sensitization was blunted in CBD-treated animals. A hypoactive metabolic response and a hyperactive metabolic response in mPFC and NAc subregions respectively were observed after the behavioral sensitization.

CBD prevented almost all these changes.

Our findings substantially contribute to the understanding of the functional changes associated with cocaine- and caffeine-induced sensitization and the effect of CBD on this process.”

https://pubmed.ncbi.nlm.nih.gov/32415526/

https://link.springer.com/article/10.1007%2Fs12640-020-00218-9

A Balanced Approach for Cannabidiol Use in Chronic Pain

Frontiers in Pharmacology (@FrontPharmacol) | Twitter “Cannabidiol (CBD), the major non-psychoactive constituent of Cannabis sativa L., has gained traction as a potential treatment for intractable chronic pain in many conditions. Clinical evidence suggests that CBD provides therapeutic benefit in certain forms of epilepsy and imparts analgesia in certain conditions, and improves quality of life.

CBD continues to be Schedule I or V on the list of controlled substances of the Drug Enforcement Agency of the United States. However, preparations labeled CBD are available publicly in stores and on the streets. However, use of CBD does not always resolve pain. CBD purchased freely entails the risk of adulteration by potentially hazardous chemicals. As well, CBD use by pregnant women is rising and poses a major health-hazard for future generations.

In this mini-review, we present balanced and unbiased pre-clinical and clinical findings for the beneficial effects of CBD treatment on chronic pain and its deleterious effects on prenatal development.”

https://pubmed.ncbi.nlm.nih.gov/32425793/

https://www.frontiersin.org/articles/10.3389/fphar.2020.00561/full

www.frontiersin.org

The Cannabis Spread Throughout the Continents and Its Therapeutic Use in History

“Historical relevance: Cannabis sativa L. (C. sativa) is a plant whose use as a therapeutic agent shares its origins with the first Far East’s human societies. Cannabis has been used not only for recreational purposes, but as a food to obtain textile fibers, to produce hemp paper, to treat many physical and mental disorders.

This review aims to provide a complete assessment of the deep knowledge of the cannabis psychoactive effects and medicinal properties in the course of history covering i.) the empirical use of the seeds and the inflorescences to treat many physical ailments by the ancient Oriental physicians ii.) the current use of cannabis as a therapeutic agent after the discovery of its key psychoactive constituent and the human endogenous endocannabinoid system.

Results and conclusion: Through a detailed analysis of the available resources about the origins of C. sativa we found that its use by ancient civilizations as a source of food and textile fibers dates back over 10,000 years, while its therapeutic applications have been improved over the centuries, from the ancient East medicine of the 2nd and 1st millennium B.C. to the more recent introduction in the Western world after the 1st century A.D. In the 20th and 21th centuries, Cannabis and its derivatives have been considered as a menace and banned throughout the world, but nowadays they are still the most widely consumed illicit drugs all over the world. Its legalization in some jurisdictions has been accompanied by new lines of research to investigate its possible applications for medical and therapeutic purposes.”

https://pubmed.ncbi.nlm.nih.gov/32433013/?from_term=cannabinoid&from_sort=date&from_size=200&from_pos=6

http://www.eurekaselect.com/182145/article

The Therapeutic Effectiveness of Full Spectrum Hemp Oil Using a Chronic Neuropathic Pain Model

life-logo“Few models exist that can control for placebo and expectancy effects commonly observed in clinical trials measuring ‘Cannabis’ pharmacodynamics. We used the Foramen Rotundum Inflammatory Constriction Trigeminal Infraorbital Nerve injury (FRICT-ION) model to measure the effect of “full-spectrum” whole plant extracted hemp oil on chronic neuropathic pain sensitivity in mice.

Results: Mechanical allodynia was alleviated within 1 h (d = 2.50, p < 0.001) with a peak reversal effect at 4 h (d = 7.21, p < 0.001) and remained significant throughout the 6 h observation window. There was no threshold change on contralateral whisker pad after hemp oil administration, demonstrating the localization of anesthetic response to affected areas.

Conclusion: Future research should focus on how whole plant extracted hemp oil affects multi-sensory and cognitive-attentional systems that process pain.

The present study shows for the first time that common, commercially available, and easily reproducible full-spectrum hemp oil induces significant anti-allodynic effects with a bell-shaped pain sensitivity effect peeking between 2 and 4 h and lasting over 6 h. The study provides evidence that phytochemical extracts of the Cannabis plant, even with relatively low levels of THC, can significantly improve mechanical pressure pain in animals with established chronic neuropathic hypersensitivity.”

https://www.mdpi.com/2075-1729/10/5/69/htm

“Legal Cannabis hemp oil effectively treats chronic neuropathic pain: study”   https://medicalxpress.com/news/2020-05-legal-cannabis-hemp-oil-effectively.html