“The treatment of traumatic spinal cord injury (SCI) remains challenging as the neuron regeneration is impaired by irregular cavity and apoptosis. An injectable in situ gelling hydrogel is therefore developed for the local delivery of cannabidiol (CBD) through a novel method based on polyelectrolyte (PEC) interaction of sodium carboxymethylcellulose (CMC) and chitosan (CS). It can be injected into the spinal cord cavity with a 26-gauge syringe before gelation, and gelled after 110 ± 10 s. Of note, the in-situ forming hydrogel has mechanical properties similar to spinal cord. Moreover, the CBD-loaded hydrogels sustain delivery of CBD for up to 72 h, resulting in reducing apoptosis in SCI by enhancing mitochondrial biogenesis. Importantly, the CBD-loaded hydrogels raise neurogenesis more than pure hydrogels both in vivo and in vitro, further achieving significant recovery of motor and urinary function in SCI rats. Thus, it suggested that CMC/CS/CBD hydrogels could be used as promising biomaterials for tissue engineering and SCI.”
“Objectives: Billions of individuals worldwide suffer from periodontal disease, an inflammatory disease that results in hard-tissue and soft-tissue destruction. A viable therapeutic option to treat periodontal disease may be via cannabinoids that exert immunomodulatory effects, and the endocannabinoid system (ECS) is readily present in periodontal tissues that exhibit cannabinoid type 1 and 2 receptors (CB1R and CB2R). Phytocannabinoids (pCBs), which are a part of a heterogeneous group of molecules acting on cannabinoid receptors (CBR) derived from the cannabis plants, have been attributed to a wide variety of effects including anti-inflammatory activity and some pro-inflammatory effects depending on the cell type. Thus, this study aims to examine the effects of pCBs on primary human gingival fibroblasts (HGFs) in IL-1β stimulated (simulated periodontal disease) HGFs.
Results: Cannabidivarin (CBVN or CBDV) (EC50 = 12 nM) and cannabigerol (CBG) (EC50 = 30 nM) exhibited agonist activity on CB2R with intermediate efficacy. Cannabidiol (CBD) did not exhibit activation of the CB2R, and the CB1R activation was not observed with any of the pCBs. Cytotoxicity results showed that concentrations of 2.50 μg/ml or greater for the pCBs were toxic except for CBVN. Lower concentrations of CBD and CBG (0.1-0.75 μg/ml), and CBVN at 2.50 μg/ml exhibited significant effects on HGF proliferation. In IL-1β-stimulated HGFs, prostaglandin E2 (PGE2) production was significantly suppressed only by CBG and CBVN. CBD and CBG treatment alone did, however, elevate PGE2 production significantly compared to control. IL-1β stimulation resulted in a robust increase in the production of all cytokines tested. Treatment of IL-β-stimulated HGF with the three pCBs (1 μg/ml) significantly reduced INF-ɣ, TNF-α, and IL-2. The significant suppression of IL-4 was seen with CBD and CBVN, while only CBVN exerted suppression of IL-13. The three pCBs significantly increased IL-6, IL-10, and IL-12 levels, while none of the pCBs reduced the expression of IL-8 in IL-1β-stimulated HGF.
Conclusion: The effective inhibition of IL-1β-stimulated production of PGE2 and cytokines by the pCB in HGFs suggests that targeting the endocannabinoid system may lead to the development of therapeutic strategies for periodontal therapy. However, each pCB has its unique anti-inflammatory profile, in which certain pro-inflammatory activities are also exhibited. The pCBs alone or in combination may benefit and aid in improving public oral health.”
“Background and purpose: Data regarding the effects of cannabidiol (CBD) on the quality of life (QOL) are currently inadequate. We assessed the QOL of pediatric patients with epilepsy who were treated with CBD.
Methods: This prospective, open-label study included pediatric and adolescent patients (aged 2-18 years) with Dravet syndrome or Lennox-Gastaut syndrome. Oral CBD was administered at 10 mg/kg/day. The Korean version of the Quality Of Life in Childhood Epilepsy (QOLCE) questionnaire was administered when CBD treatment began and again after 6 months. Adaptive behavior was measured using the Korean versions of the Child Behavior Checklist (K-CBCL) and the second edition of the Vineland Adaptive Behavior Scales (Vineland-II).
Results: This study included 41 patients (11 with Dravet syndrome and 30 with Lennox-Gastaut syndrome), of which 25 were male. The median age was 4.1 years. After 6 months, 26.8% (11/41) of patients experienced a ≥50% reduction in the number of seizures. The total score for the QOLCE questionnaire did not change from baseline to after 6 months of CBD treatment (85.71±39.65 vs. 83.12±48.01, respectively; p=0.630). The score in the motor skills domain of Vineland-II reduced from 48.67±13.43 at baseline to 45.18±14.08 after 6 months of treatment (p=0.005). No other Vineland-II scores and no K-CBCL scores had changed after 6 months of CBD treatment.
Conclusions: CBD is an efficacious antiseizure drug used to treat Dravet syndrome and Lennox-Gastaut syndrome. However, it did not improve the patient QOL in our study, possibly because all of our patients had profound intellectual disabilities.”
“Background: Alcohol binge drinking may compromise the functioning of the nucleus accumbens (NAc), i.e. the neural hub for processing reward and aversive responses.
Methods: As socially stressful events pose particular challenges at developmental stages, this research applied the resident-intruder paradigm as a model of social stress, to highlight behavioural neuroendocrine and molecular maladaptive plasticity in rats at withdrawal from binge-like alcohol exposure in adolescence. In search of a rescue agent, cannabidiol (CBD) was selected due to its favourable effects on alcohol- and stress-related harms.
Results: Binge-like alcohol exposed intruder rats displayed a compromised defensive behaviour against the resident and a blunted response of the stress system, in addition to indexes of abnormal dopamine (DA)/glutamate plasticity and dysfunctional spine dynamics in the NAc. CBD administration (60 mg/kg) was able to: (1) increase social exploration in the binge-like alcohol exposed intruder rats, at the expenses of freezing time, and in control rats, which received less aggressive attacks from the resident; (2) reduce corticosterone levels independently on alcohol previous exposure; (3) restore DA transmission and (4) facilitate excitatory postsynaptic strength and remodelling.
Conclusions: Overall, the maladaptive behavioural and synaptic plasticity promoted by the intersection between binge-like alcohol withdrawal and exposure to adverse social stress can be rescued by a CBD détente effect that results in a successful defensive strategy, supported by a functional endocrine and synaptic plasticity. The current data highlight CBD’s relevant therapeutic potential in alcohol- and stress-related harms, and prompt further investigation on its molecular targets.”
“Dogs are commonly affected by Osteoarthritis (OA). Different approaches can be used to alleviate animals’ symptoms. In this randomised, placebo-controlled and double-blind clinical trial, we performed a three months follow-up study assessing the efficacy of a food supplement containing natural ingredients (Cannabis sativa oil, Boswellia serrata Roxb. Phytosome® and Zingiber officinale extract) in dogs with OA after the interruption of physiotherapy that was performed during the previous three months. Inflammation and oxidative stress were reduced in the treated group (higher glutathione (GSH) and lower C-reactive protein [CRP] levels in blood) as well as chronic pain.”
“Cannabis sativa L. has been known for at least 2000 years as a source of important, medically significant specialised metabolites and several bio-active molecules have been enriched from multiple chemotypes. However, due to the many levels of complexity in both the commercial cultivation of cannabis and extraction of its specialised metabolites, several heterologous production approaches are being pursued in parallel.
In this review, we outline the recent achievements in engineering strategies used for heterologous production of cannabinoids, terpenes and flavonoids along with their strength and weakness. We provide an overview of the specialised metabolism pathway in C. sativa and a comprehensive list of the specialised metabolites produced along with their medicinal significance.
We highlight cannabinoid-like molecules produced by other species. We discuss the key biosynthetic enzymes and their heterologous production using various hosts such as microbial and eukaryotic systems. A brief discussion on complementary production strategies using co-culturing and cell-free systems is described. Various approaches to optimise specialised metabolite production through co-expression, enzyme engineering and pathway engineering are discussed. We derive insights from recent advances in metabolic engineering of hosts with improved precursor supply and suggest their application for the production of C. sativa speciality metabolites.
We present a collation of non-conventional hosts with speciality traits that can improve the feasibility of commercial heterologous production of cannabis-based specialised metabolites. We provide a perspective of emerging research in synthetic biology, allied analytical techniques and plant heterologous platforms as focus areas for heterologous production of cannabis specialised metabolites in the future.”
“Background: Several retrospective studies on pediatric epilepsy reported positive effects of cannabidiol-enriched artisanal cannabis oil and pure cannabidiol oil on seizure reduction.
Methods: This is a retrospective study of children and adolescents with refractory epilepsy caused by various etiologies who were treated with artisanal cannabis oil during January 2014 to June 2019, with at least one year follow-up.
Results: Of 114 patients, 84 (73.3%) reported some improvement in seizure frequency at some point during treatment. Fifty-one (59%) of the 86 patients who continued treatment for at least one year showed >50% improvement in seizure frequency. Seizure etiology, seizure type, and patients’ age and sex were not found to be associated with the response to cannabidiol-enriched cannabis oil. Side effects were minor, and positive effects beyond seizure reduction were noted.
Conclusions: Artisanal cannabidiol-enriched cannabis may be an effective and safe long-term treatment for refractory epilepsy.”
“Women present increased susceptibility to anxiety- and stress-related disorders compared to men. A potentially promising pharmacological-based strategy to regulate abnormal aversive memories disrupts their reconsolidation stage after reactivation and destabilization.
Male rodent findings indicate that cannabidiol (CBD), a relatively safe and effective treatment for several mental health conditions, can impair the reconsolidation of aversive memories. However, whether and how CBD influences it in females is still unknown.
The present study addressed this question in contextually fear-conditioned female rats.
We report that systemically administered CBD impaired their reconsolidation, reducing freezing expression for over a week. This action was restricted to a time when the reconsolidation presumably lasted (< six hours post-retrieval) and depended on memory reactivation/destabilization. Moreover, the impairing effects of CBD on memory reconsolidation relied on the activation of cannabinoid type-1 but not type-2 receptors located in the CA1 subregion of the dorsal hippocampus.
CBD applied directly to this brain area was sufficient to reproduce the effects of systemic CBD treatment. Contextual fear memories attenuated by CBD did not show reinstatement, an extinction-related feature. By demonstrating that destabilized fear memories are sensitive to CBD and how it hinders mechanisms in the DH CA1 that may restabilize them in female rats, the present findings concur that reconsolidation blockers are viable and could be effective in disrupting abnormally persistent and distressing aversive memories such as those related to posttraumatic stress disorder.”
“Introduction: Amotivational syndrome is a term used to refer to lack of motivation and passive personality related to chronic cannabis use. Given mixed findings, the current study aimed to replicate and extend previous research on frequent cannabis use, motivated behavior, and self-reported apathy.
Method: Cannabis users (on average, ≥3 days/week of cannabis use over the past year), and healthy controls (≤1 day/month of cannabis use over the past year) completed the Apathy Evaluation Scale (AES), and the Effort Expenditure for Rewards Task (EEfRT). Repeated measures analysis of covariance was used to 1) examine the effects of group, reward magnitude, probability, and their interaction on hard task selections on the EEfRT, and 2) examine between-group differences on the AES, controlling for alcohol use and depressive symptoms.
Results: There were significant main effects of reward magnitude, probability, and an interaction between reward magnitude and probability on hard task selection (p‘s < 0.05). Specifically, as reward magnitude and probability of winning the reward increased, participants were more likely to select hard tasks on the EEfRT. Relative to healthy controls, cannabis users were significantly more likely to select hard tasks on the EEfRT (F(1,56) = 6.49, p = 0.014, ηp2= 0.10). When controlling for alcohol use and depressive symptoms, no significant group differences in self-reported apathy were present (p = 0.46).
Conclusions: Cannabis users exhibit a greater likelihood of exerting more effort for reward, suggesting enhanced motivation relative to healthy controls. Thus, the current results do not support amotivational syndrome in adult frequent cannabis users. Despite some harms of long-term cannabis use, amotivation may not be among them.”
“Effort-related decision making and cannabis use among college students. The results provide preliminary evidence suggesting that college students who use cannabis are more likely to expend effort to obtain reward, even after controlling for the magnitude of the reward and the probability of reward receipt. Thus, these results do not support the amotivational syndrome hypothesis.”
“Background: Cannabis use may be linked with anhedonia and apathy. However, previous studies have shown mixed results and few have examined the association between cannabis use and specific reward sub-processes. Adolescents may be more vulnerable to harmful effects of cannabis than adults. This study investigated (1) the association between non-acute cannabis use and apathy, anhedonia, pleasure, and effort-based decision-making for reward, and (2) whether these relationships were moderated by age-group.
Methods: We used data from the ‘CannTeen’ study. Participants were 274 adult (26-29 years) and adolescent (16-17 years) cannabis users (1-7 days/week use in the past three months), and gender- and age-matched controls. Anhedonia was measured with the Snaith-Hamilton Pleasure Scale (n=274), and apathy was measured with the Apathy Evaluation Scale (n=215). Effort-based decision-making for reward was measured with the Physical Effort task (n=139), and subjective wanting and liking of rewards was measured with the novel Real Reward Pleasure task (n=137).
Results: Controls had higher levels of anhedonia than cannabis users (F1,258=5.35, p=.02, ηp2=.02). There were no other significant effects of User-Group and no significant User-Group*Age-Group interactions. Null findings were supported by post hoc Bayesian analyses.
Conclusion: Our results suggest that cannabis use at a frequency of three to four days per week is not associated with apathy, effort-based decision-making for reward, reward wanting, or reward liking in adults or adolescents. Cannabis users had lower anhedonia than controls, albeit at a small effect size. These findings are not consistent with the hypothesis that non-acute cannabis use is associated with amotivation.”
