“Substances from the Cannabis sativa species, especially cannabidiol (CBD) and Delta-9-tetrahydrocannabinol (Δ9-THC), have attracted medical attention in recent years. The actions of these two main cannabinoids modulate the cholinergic nervous system (CholNS) involving development, synaptic plasticity, and response to endogenous and environmental damage, as a characteristic of many neurodegenerative diseases.
The dynamics of these diseases are mediated by specific neurotransmitters, such as the GABAergic nervous system (GNS) and the CholNS. The nematode Caenorhabditis elegans is an important experimental model, which has different neurotransmitter systems that coordinate its behavior and has a transgene strain that encodes the human β-amyloid 1-42 peptide in body wall muscle, one of the main proteins involved in Alzheimer´s disease.
Therefore, the objective of this study was to evaluate the protective potential of terpenoids found in C. sativa in the GNS and CholNS of C. elegans. The effect of two C. sativa oils with variations in CBD and THC concentrations on acetylcholinesterase (AChE) activity, lipid peroxidation, and behavior of C. elegans was evaluated.
C. sativa oils were efficient in increasing pharyngeal pumping rate and reducing defecation cycle, AChE activity, and ROS levels in N2 strains. In the muscle:Abeta1-42 strain, mainly when using CBD oil, worm movement, body bends, and pharyngeal pumping were increased, with a reduced AChE activity.
Consequently, greater investments in scientific research are needed, in addition to breaking the taboo on the use of the C. sativa plant as an alternative for medicinal use, especially in neurodegenerative diseases, which have already shown positive initial results.”
“Cannabis has been used in even the oldest traditional medicines available. In the last century, negative attention has prevailed regarding the psychotropic and abuse potential. For this reason, Cannabis has been banned and declared illegal in many countries. In recent years, however, there has been a more in-depth evaluation of the legalization of cannabinoids for medical use in several countries following heightened media attention and reports of effectiveness, although not always thoroughly backed up by scientific evidence. The official introduction of pharmaceutical-grade Cannabis inflorescences for medicinal purposes has allowed physicians and pharmacists, to prescribe and prepare several Cannabis preparations legally. Such products are currently being administered to patients without their efficacy being evaluated in controlled studies: for each patient the composition and route of administration may differ. In addition, many advanced administration systems have been developed or are still under development, but few clinical trials have been completed.
In this context, this Research Topic focused on the in-depth analysis of the legal, technological and pharmacological aspects related to the medical use of Cannabis-based formulations.
Anil et al. have directed their research specifically on the activity of Cannabis for medical use in the context of inflammatory processes. Although activities in this area are plausible, the high number of active molecules produced by Cannabis and simultaneously administered through the extractive products normally used in therapy, has not yet made it possible to identify their specific mechanisms of action. Once the modalities of action of the active molecules have been clarified, it might be of interest to use purified mixtures to obtain a more significant activity potentially (Anil et al.).
Specific literature reviews were then done for some pathologies such as when Xin et al. investigated the potential therapeutic effect of CBD in bone diseases. Even in this case, further studies are needed to evaluate the benefits and risks of cannabinoids’ use (Xin et al.).
A large part of the clinical research relating to Cannabis for medical use concerns its use in the context of diseases of the central nervous system. Ortiz et al. examined evidence supporting the therapeutic utility of cannabinoids for treating neurodegenerative diseases, pain, mood disorders, and substance use disorders. Important considerations were also made on the methods of formulation and the routes of administration (Ortiz et al.). Lacroix et al. Also considered Cannabis in neurological disorders stressing that currently most of the scientific data supports the potential therapeutic use of Cannabis but, as much as patients request it, the knowledge is still too little in-depth. It is therefore certainly urgent to manage clinical trials to provide stronger and safer evidence (Lacroix et al.).
Procaccia et al. discussed how phytocannabinoid profiles differed between plants according to chemovar types and examined the main factors influencing the accumulation of secondary metabolites in the plant, including genotype, growing conditions, processing, storage and the delivery route; the authors highlighted how these factors make the use of Cannabis in therapy highly complex (Procaccia et al.).
In addition to the more well-known compounds such as THC and CBD, Cannabis produces over 120 other phytocannabinoids. The use of THC is associated with acute psychotropic effects that could potentially be avoided considering that minor cannabinoids and their chemical counterparts could offer the same potential benefits without the same adverse effects. In this regard, Walsh et al. reviewed the literature to provide an overview of the endocannabinoid system, phytocannabinoid biosynthesis and a discussion on molecular pharmacology. Potential therapeutic uses of minor cannabinoids underlining that future studies will have to rigorously evaluate these compounds’ risk/benefit ratio (Walsh et al.).
The interest in molecules other than cannabinoids such as terpenes is certainly relevant. This interest has grown even greater since the possibility of an “entourage” effect between the active molecules of Cannabis has been postulated. Accordingly, Finlay et al. in their study examined whether some terpenes acted directly on cannabinoid receptors. From the results obtained, it was not possible to exclude the existence of an entourage effect. Still, this cannot be linked to a direct action of the terpenes on the cannabinoid receptors. However, the pharmacological mechanism underlying this substances activity remains to be thoroughly investigated (Finlay et al.).
Maayah et al. pointed out that full-spectrum Cannabis extracts have been used in clinical trials to treat various diseases. However, despite their efficacy, their potential use in therapy may be limited by possible behavioural side effects. These researchers then successfully worked on experimental animals to identify a panel of blood metabolites predicting behavioural effects (Maayah et al.).
Pennypacker et al. have evaluated whether the products available on the market in the United States of America are consistent in the concentration of cannabinoids, with the literature indications for use in therapy. Overall, the results of this study have been defined by the authors as alarming as current product offerings do not reflect scientific evidence (Pennypacker et al.).
In the regulatory context MacPhail et al. have analysed the trend of prescriptions in Australia over the last 5 years, noting a substantial increase in prescriptions over time that does not actually reflect a worsening of the pathological conditions of the population but rather a greater prescription linked to greater knowledge and acceptance of this type of therapy (MacPhail et al.).
As regards the use in therapy of medical Cannabis, the current regulations have been analysed by Baratta et al. in those countries where clinical studies have recently been conducted. The results of the trials have been crossed with the pathologies for which the current legislation provides that it is possible to prescribe Cannabis allowing relevant considerations (Baratta et al.).
From all the publications collected, it is clear that there is a great interest in the enormous potential of Cannabis in the medical field but also a widespread awareness of the extreme need to conduct in-depth research that clarifies the mechanisms of action of the quantity of components present in the phytocomplex of this plant species.”
“Cannabis sativa contains more than 120 cannabinoids and 400 terpene compounds (i.e., phytomolecules) present in varying amounts. Cannabis is increasingly available for legal medicinal and non-medicinal use globally, and with increased access comes the need for a more comprehensive understanding of the pharmacology of phytomolecules. The main transducer of the intoxicating effects of Cannabis is the type 1 cannabinoid receptor (CB1R). ∆9-tetrahydrocannabinolic acid (∆9-THCa) is often the most abundant cannabinoid present in many cultivars of Cannabis. Decarboxylation converts ∆9-THCa to ∆9-THC, which is a CB1R partial agonist. Understanding the complex interplay of phytomolecules-often referred to as “the entourage effect”-has become a recent and major line of inquiry in cannabinoid research. Additionally, this interest is extending to other non-Cannabis phytomolecules, as the diversity of available Cannabis products grows. Here, we chose to focus on whether 10 phytomolecules (∆8-THC, ∆6a,10a-THC, 11-OH-∆9-THC, cannabinol, curcumin, epigallocatechin gallate, olivetol, palmitoylethanolamide, piperine, and quercetin) alter CB1R-dependent signaling with or without a co-treatment of ∆9-THC. Phytomolecules were screened for their binding to CB1R, inhibition of forskolin-stimulated cAMP accumulation, and βarrestin2 recruitment in Chinese hamster ovary cells stably expressing human CB1R. Select compounds were assessed further for cataleptic, hypothermic, and anti-nociceptive effects on male mice. Our data revealed partial agonist activity for the cannabinoids tested, as well as modulation of ∆9-THC-dependent binding and signaling properties of phytomolecules in vitro and in vivo. These data represent a first step in understanding the complex pharmacology of Cannabis– and non-Cannabis-derived phytomolecules at CB1R and determining whether these interactions may affect the physiological outcomes, adverse effects, and abuse liabilities associated with the use of these compounds.”
“The endocannabinoid system is located throughout the central and peripheral nervous systems, endocrine system, gastrointestinal system, and within inflammatory cells. The use of medical cannabinoids has been gaining traction as a viable treatment option for varying illnesses in recent years. Research is ongoing looking at the effect of cannabinoids for treatment of common otolaryngologic pathologies. This article identifies common otolaryngologic pathologies where cannabinoids may have benefit, discusses potential drawbacks to cannabinoid use, and suggests future directions for research in the application of medical cannabinoids.”
“Ovarian cancer (OC) is the most lethal gynecological malignancy, with about 70% of cases diagnosed only at an advanced stage.
Cannabis sativa, which produces more than 150 phytocannabinoids, is used worldwide to alleviate numerous symptoms associated with various medical conditions. Recently, studies across a range of cancer types have demonstrated that the phytocannabinoids Δ9-trans-tetrahydrocannabinol (THC) and cannabidiol (CBD) have anti-cancer activity in vitro and in vivo, but also the potential to increase other drugs’ adverse effects.
THC and CBD act via several different biological and signaling pathways, including receptor-dependent and receptor-independent pathways. However, very few studies have examined the effectiveness of cannabis compounds against OC. Moreover, little is known about the effectiveness of cannabis compounds against cancer stem cells (CSCs) in general and OC stem cells (OCSCs) in particular. CSCs have been implicated in tumor initiation, progression, and invasion, as well as tumor recurrence, metastasis, and drug resistance. Several hallmarks and concepts describe CSCs. OCSCs, too, are characterized by several markers and specific drug-resistance mechanisms.
While there is no peer-reviewed information regarding the effect of cannabis and cannabis compounds on OCSC viability or development, cannabis compounds have been shown to affect genetic pathways and biological processes related to CSCs and OCSCs. Based on evidence from other cancer-type studies, the use of phytocannabinoid-based treatments to disrupt CSC homeostasis is suggested as a potential intervention to prevent chemotherapy resistance. The potential benefits of the combination of chemotherapy with phytocannabinoid treatment should be examined in ovarian cancer patients.”
“Ovarian cancer is the most lethal gynecological malignancy. Cancer stem cells have been implicated in tumor initiation, progression, and invasion, as well as tumor recurrence, metastasis, and drug resistance. Cannabis is used worldwide to alleviate numerous symptoms associated with various medical conditions. Phytocannabinoids, produced by cannabis, were shown to have anti-cancer activity in cell lines and animal models, but also the potential to increase other drugs’ adverse effects. Yet, very few studies have examined the effectiveness of cannabis compounds against ovarian cancer. Cannabis compounds have been shown to affect genetic pathways and biological processes related to development of ovarian cancer stem cells. Phytocannabinoid-based treatments might be used to disrupt cancer stem cell homeostasis and thereby to prevent chemotherapy resistance. The potential benefits of the combination of chemotherapy with phytocannabinoid treatment could be examined in ovarian cancer patients.”
“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.”
“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.”
“Steroids and endocannabinoids are part of two modulatory systems and some evidence has shown their interconnections in several functions.
Homeostasis is a common steady-state described in the body, which is settled by regulatory systems to counterbalance deregulated or allostatic set points towards an equilibrium. This regulation is of primary significance in the central nervous system for maintaining neuronal plasticity and preventing brain-related disorders.
In this context, the recent discovery of the shutdown of the endocannabinoid system (ECS) overload by the neurosteroid pregnenolone has highlighted new endogenous mechanisms of ECS regulation related to cannabis-induced intoxication.
These mechanisms involve a regulatory loop mediated by overactivation of the central type-1 cannabinoid receptor (CB1R), which triggers the production of its own regulator, pregnenolone. Therefore, this highlights a new process of regulation of steroidogenesis in the brain.
Pregnenolone, long considered an inactive precursor of neurosteroids, can then act as an endogenous negative allosteric modulator of CB1R. The present review aims to shed light on a new framework for the role of ECS in the addictive characteristics of cannabis with the novel endogenous mechanism of ECS involving the neurosteroid pregnenolone.
In addition, this new endogenous regulatory loop could provide a relevant therapeutic model in the current context of increasing recreational and medical use of cannabis.”
“Alzheimer’s disease (AD) is the most common form of dementia, but there is still no available treatment.
Δ9-tetrahydrocannabinol (THC) is emerging as a promising therapeutic agent. Using THC in conventional high doses may have deleterious effects. Therefore, we propose to use an ultra-low dose of THC (ULD-THC). We previously published that a single injection of ULD-THC ameliorated cognitive functioning in several models of brain injuries as well as in naturally aging mice.
Here, 5xFAD AD model mice received a single treatment of ULD-THC (0.002 mg/kg) after disease onset and were examined in two separate experiments for cognitive functions, neurotropic, and inflammatory factors in the hippocampus.
We show that a single injection of ULD-THC alleviated cognitive impairments in 6- and 12-month-old 5xFAD mice. On the biochemical level, our results indicate an imbalance between the truncated TrkB receptor isoform and the full receptor, with AD mice showing a greater tendency to express the truncated receptor, and ULD-THC improved this imbalance. We also investigated the expression of three AD-related inflammatory markers and found an ameliorating effect of ULD-THC.
The current research demonstrates for the first time the beneficial effects of a single ultra-low dose of THC in a mouse model of AD after disease onset.”
“The current research demonstrates for the first time the beneficial effects of a single ultra-low dose of THC in a mouse model of AD after disease onset. As THC is a cheap, widely available substance already approved for use in other conditions, this research brings us closer to understanding its mechanisms and will possibly lead to new treatments.”
