“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.”
“Purpose of review: There have been many debates, discussions, and published writings about the therapeutic value of cannabis plant and the hundreds of cannabinoids it contains. Many states and countries have attempted, are attempting, or have already passed bills to allow legal use of cannabinoids, especially cannabidiol (CBD), as medicines to treat a wide range of clinical conditions without having been approved by a regulatory body. Therefore, by using PubMed and Google Scholar databases, we have reviewed published papers during the past 30 years on cannabinoids as medicines and comment on whether there is sufficient clinical evidence from well-designed clinical studies and trials to support the use of CBD or any other cannabinoids as medicines.
Recent findings: Current research shows that CBD and other cannabinoids currently are not ready for formal indications as medicines to treat a wide range of clinical conditions as promoted except for several exceptions including limited use of CBD for treating two rare forms of epilepsy in young children and CBD in combination with THC for treating multiple-sclerosis-associated spasticity.
Summary: Research indicates that CBD and several other cannabinoids have potential to treat multiple clinical conditions, but more preclinical, and clinical studies and clinical trials, which follow regulatory guidelines, are needed to formally recommend CBD and other cannabinoids as medicines.”
“Based on preliminary preclinical and clinical research, cannabinoids could be further investigated for their potential in treating a wide range of clinical conditions. For their effects on neuroinflammation, inflammatory cytokines, psychosis, fibrosis, and immunomodulation, many of these cannabinoids may be further investigated for treating clinical indications ranging from seizures/epilepsy in adults, schizophrenia, obesity, nausea, neuropathy, retinopathy nephropathy, pain, and dermal conditions like dermatitis and acne.”
“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.”
“While blockade of cannabinoid receptor 1 (CB1) has been shown to attenuate diet-induced obesity (DIO), its relative role in different cell types has not been tested. The current study investigated the role of CB1 in immune vs non-immune cells during DIO by generating radiation-induced bone marrow chimeric mice that expressed functional CB1 in all cells except the immune cells or expressed CB1 only in immune cells. CB1-/- recipient hosts were resistant to DIO, indicating that CB1 in non-immune cells is necessary for induction of DIO. Interestingly, chimeras with CB1-/- in immune cells showed exacerbation in DIO combined with infiltration of bone-marrow-derived macrophages to the brain and visceral adipose tissue, elevated food intake, and increased glucose intolerance. These results demonstrate the opposing role of CB1 in hematopoietic versus non-hematopoietic cells during DIO and suggests that targeting immune CB1 receptors provides a new pathway to ameliorate obesity and related metabolic disorders.”
“Peripheral inputs continuously shape brain function and can influence memory acquisition, but the underlying mechanisms have not been fully understood. Cannabinoid type-1 receptor (CB1R) is a well-recognized player in memory performance, and its systemic modulation significantly influences memory function. By assessing low arousal/non-emotional recognition memory in mice, we found a relevant role of peripheral CB1R in memory persistence. Indeed, the peripherally-restricted CB1R specific antagonist AM6545 showed significant mnemonic effects that were occluded in adrenalectomized mice, and after peripheral adrenergic blockade. AM6545 also transiently impaired contextual fear memory extinction. Vagus nerve chemogenetic inhibition reduced AM6545-induced mnemonic effect. Genetic CB1R deletion in dopamine β-hydroxylase-expressing cells enhanced recognition memory persistence. These observations support a role of peripheral CB1R modulating adrenergic tone relevant for cognition. Furthermore, AM6545 acutely improved brain connectivity and enhanced extracellular hippocampal norepinephrine. In agreement, intra-hippocampal β-adrenergic blockade prevented AM6545 mnemonic effects. Altogether, we disclose a novel CB1R-dependent peripheral mechanism with implications relevant for lengthening the duration of non-emotional memory.”
“Cannabis has been used in medicine for thousands of years, yet its use for therapeutic purposes is still controversial. Meta-analysis of the literature has shown the effectiveness of cannabinoids only in some diseases. Researchers are particularly interested in their use in chronic pain management, which analgesic effect has been proved in many studies. A review of the literature indicates that cannabinoid preparations may be effective in the treatment of some chronic pain disorders, particularly in neuropathic pain, and should be considered as a possible therapeutic choice in the absence of a satisfactory analgesic effect with standard medications. The increasing number of countries approving cannabinoids for medical use creates an opportunity to conduct more clinical trials and collect better-quality data necessary to establish clear guidelines and consistent recommendations for specific pain disorders.”
“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.”
“Pain is a highly debilitating emotional and sensory experience that significantly affects quality of life (QoL). Numerous chronic conditions, including cancer, are associated with chronic pain. In the setting of malignancy, pain can be a consequence of the tumor itself or of life-saving interventions, including surgery, chemotherapy, and radiotherapy. Despite significant pharmacological advances and awareness campaigns, pain remains undertreated in one-third of patients. To date, opioids have been the mainstay of cancer pain management. The problematic side effects and unsatisfactory pain relief of opioids have revived patients’ and physicians’ interest in finding new solutions, including cannabis and cannabinoids. The medical use of cannabis has been prohibited for decades, and it remains in Schedule 1 of the Misuse of Drugs Regulations. Currently, the legal context for its usage has become more permissive. Various preclinical and observational studies have aimed to prove that cannabinoids could be effective in cancer pain management. However, their clinical utility must be further supported by high-quality clinical trials.”
