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Phytocannabinoids and Cannabimimetic Drugs: Recent Patents in Central Nervous System Disorders
Abstract and Figures
Background:
Starting from the chemical structure of phytocannabinoids, isolated from Cannabis sativa plant, research groups designed numerous cannabimimetic drugs. These compounds according to their activities can be partial, full agonists and antagonists of cannabinoid receptors. Anecdotal reports and scientific studies described beneficial properties of cannabinoids and their derivatives in several pathological conditions like neurological and neuropsychiatric disorders, and in many other diseases ranging from cancer, atherosclerosis, stroke, hypertension, inflammatory related disorders, and autoimmune diseases.
Methods:
In this study, starting from the endocannabinoid mechanism of action in neuronal signaling, we highlight and discuss potential application and recent patents of cannabimimetic drugs in neurological disorders.
Results:
The cannabinoid CB1 receptor was considered particularly interesting for therapeutic approaches in neurological diseases, because primarily expressed by neurons of the central nervous system. In many experimental models, these drugs act via this receptor, however, CB1 receptor independent mechanisms have been also described. Furthermore, endogenous ligands of cannabinoid receptors, the endocannabinoids, are potent modulators of the synaptic function in the brain. In neurological diseases, numerous studies reported modulation of the levels of endocannabinoids according to the phase of the disease and its progression.
Conclusions:
Finally, although the study of the mechanisms of action of these compounds is still unsolved, many reports and patents strongly suggest therapeutic potential of these compounds in neurological diseases.
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... A synthetic analog of THC, Nabilone 179 (Cesamet ® , Meda Pharmaceuticals Inc.; 180 Canemes ® , AOPOrphan Pharmaceuticals AG), 181 is also approved since the 1980s for the treatment 182 of nausea and vomiting associated with cancer 183 chemotherapy by the FDA and by some 184 European countries (Whiting et al. 2015;185 Abuhasira et al. 2018;Bramness et al. 2018 Adapted from the following references: Koppel et al. 2014;Whiting et al. 2015;Abuhasira et al. 2018;Bramness et al. 2018;MacCallum and Russo 2018;McCoy et al. 2018 CBD cannabidiol, THC tetrahydrocannabinol 212 this is thought to be the main mechanism of action 213 of this phytocannabinoid (Izzo et al. 2009;214 Weinstein et al. 2016;Colizzi and Bhattacharyya 215 2017;Sagar and Gruber 2018;Schonhofen et al. 216 2018). The cannabinoid receptors, their ligands 217 (the endocannabinoids anandamide (AEA) and 218 2-arachidonoylglycerol (2-AG)), and the 219 enzymes responsible for the synthesis and degra-220 dation of the endocannabinoids (fatty acid amide 221 hydrolase (FAAH) and monoacylglycerol lipase 222 (MAGL)) form the endocannabinoid system 223 (ECS) (Ranieri et al. 2016;Schonhofen et al. 224 2018). The CB 1 receptoris distributed throughout 225 the brain, with particularly high densities in the 226 amygdala, hippocampus, striatum, frontal/pre-227 frontal cortex, and motor areas. ...
... CB 2 receptors are expressed in both the 239 brain and peripheral organs and are involved in 240 homeostasis, pain, and inflammation. The ECS is 241 also implicated in the growth, differentiation, 242 positioning, and connectivity among neurons 243 and in neuroplasticity, including neurogenesis 244 (Ranieri et al. 2016;Weinstein et al. 2016;245 Sagar and Gruber 2018;Schonhofen et al. 2018). ...
... 322 Recent preclinical studies showed that this 323 phytocannabinoid has antiepileptic effects that 324 seem to be independent of CB 1/2 receptors (Hill 325 et al. 2012(Hill 325 et al. , 2013. Furthermore, CBDV inhibits 326 anandamide uptake and the synthetic enzyme of 327 2-AG and activates transient receptor potential of 328 vanilloidtypes 1-2 (TRPV1/2) and TRPA1 329 channels (Hill et al. 2012(Hill et al. , 2013Iannotti et al. 330 2014;dos Santos et al. 2015;Ranieri et al. 2016;331 Morales et al. 2017).CBDV(800 mg once daily 332 over 5 days) was well tolerated in phase I and II 333 trials, and it is being investigated to treat seizure 334 disorders, Rett syndrome, and autism spectrum The action of THC as a partial agonist at CB 1/ 393 2 receptors, but especially at the CB 1 receptor, is 394 its main mechanism of action, being responsible 395 for the characteristic effects of cannabis: eupho-396 ria/dysphoria, relaxation/anxiety, and changes in 397 perceptions and thought content/psychotic 398 symptoms. As mentioned above, the CB 1 receptor 399 is high in brain areas related to emotion and 400 cognition, including the amygdala, hippocampus, 401 striatum, and prefrontal cortex. ...
Cannabis can synthetize more than 400 compounds, including terpenes, flavonoids, and more than 100 phytocannabinoids. The main phytocannabinoids are Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Cannabis-based products are used as medicines in several countries. In this text, we present an overview of the main neurochemical mechanisms of action of the phytocannabinoids, especially THC and CBD. We also reviewed the indications and adverse effects of the main cannabis-based medicinal products. THC acts as a partial agonist at cannabinoid 1/2 receptors (CB 1/2). It is responsible for the characteristic effects of cannabis, such as euphoria, relaxation, and changes in perceptions. THC can also produce dysphoria, anxiety, and psychotic symptoms. THC is used therapeutically in nausea and vomiting due to chemotherapy, as an appetite stimulant, and in chronic pain. CBD acts as a noncompetitive negative allosteric modulator of the CB 1 receptor, as an inverse agonist of the CB 2 receptor, and as an inhibitor of the reuptake of the endocannabinoid anandamide. Moreover, CBD also activates 5-HT 1A serotonergic receptors and vanilloid receptors. Its use in treatment-resistant epilepsy syndromes is approved in some countries. CBD does not produce the typical effects associated with THC and has anxiolytic and antipsychotic effects. Some of the most common adverse effects of CBD are diarrhea, somnolence, nausea, and transaminase elevations (with concomitant use of antiepileptics). The mechanisms of action involved in both the therapeutic and adverse effects of the phytocannabinoids are not fully understood, involving not only the endocannabinoid system. This "promiscuous" pharmacology could be responsible for their wide therapeutic spectrum.
... Among these plants cannabis is a common source and has anti-cancer, anti-inflammatory analgesic properties (Lötsch et al. 2018). Tetrahydrocannabinol is a monoterpene from cannabis that has been found to reduce depression and anxiety related disorders in humanns (Ranieri et al. 2015). Averol is sesquiterpene that has been utilised against AIDS virus in humans (Ranieri et al. 2015). ...
... Tetrahydrocannabinol is a monoterpene from cannabis that has been found to reduce depression and anxiety related disorders in humanns (Ranieri et al. 2015). Averol is sesquiterpene that has been utilised against AIDS virus in humans (Ranieri et al. 2015). Similarly in Artemisia annua, trichomes are the source of artemisinin a sesquiterpene lactone that is used to treat malaria (Chadwick et al. 2013). ...
Trichomes are specialized structures derived from epidermal cells. Apart from providing protection to plants, trichomes are source of medicinally important compounds. Although genes involved in initiation and patterning of trichomes have been characterized in some plants like Arabidopsis thaliana, but our knowledge about the development of these trichomes is still limited. Recent studies confirm the role of different transcription factors in trichome development of plants. In model plant Arabidopsis different transcription factor families have been studied in detail. It has been found that transcription factors like bHLH, R2R3 MYB form an activation complex with TTG1 which initiate trichome formation while as R3 MYB type transcription factors inhibit the formation of activation complex. The activation complex acts as a major trigger in the regulation of trichome development. It would be interesting to know whether such activation complex occurs in other plants like Nicotiana tobaccum, Lycopersicum esculentum, Artemisia annua etc. In this review, we focus on recent updates on transcriptional regulation of trichome development and conservation of these regulators in various species of pharmacologically and economically important plants. We have briefly discussed the cross talk of transcription factors with different hormones during trichome development. Further we have elaborated fundamental research ideologies on trichome development and translation of this research from model plant to plants of industrial interest.
... 6,7 The CB 2 receptor is also well described in myocardium, vascular endothelium, and smooth muscle. Our body synthesizes endocannabinoid molecules, and the primary endogenous signaling molecules are N-arachidonoylethanolamine (also known as AEA or anandamide) and 2-arachidonoylglycerol. 8 Both anandamide and 2-arachidonoylglycerol are agonists at CB 1 and CB 2 receptors. ...
... Over 100 distinct phytocannabinoids have been isolated from cannabis. 8 Concentrations of cannabinoids in cannabis vary considerably depending on the cannabis strain and horticultural techniques. ...
Medicolegal realities surrounding “medical marijuana” or “medical cannabis” are rapidly evolving in the United States. Clinicians are increasingly being asked by patients to share information about or certify them for medical cannabis. In order to engage in informed discussions with patients or be comfortable certifying them in states with medical cannabis laws, clinicians may benefit from an understanding of the current state of medical knowledge about medical cannabis. Intended for the generalist and subspecialist, this review provides an overview of the legal status, pharmacology, benefits, risks, and abuse liability of medical cannabis along with a general framework for counseling patients.
... Numerous articles have been published regarding cannabis plants and IPR but they are focused and localized to either a specific geographical territory (Rowand and Mcmahon 2018), a specific type of IPR (Jacobs 2017), specific fields in the cannabis plant industry (Flores-Sanchez and Ramos-Valdivia 2017; Gerra et al. 2010;Ranieri et al. 2016) or a specific species of Cannabis (Hahn 2019). Therefore, there is still a need for a broader analysis of IPR data concerning cannabis plants. ...
The purpose of this review is to advance the field of applied cannabis research by providing insights into the patenting of medical cannabis and current intellectual property rights (IPR) data.
Medical cannabis (MC) patent and plant breeders’ rights (PBR) registrations are filed on industrially applicable aspects of research. Studying the filing data and trends informs researchers of both gaps in current applied knowledge in MC (where patents have not been filed) and prior knowledge (where patents have already been filed).
Our focus is on those intellectual property rights (IPR) that are registered and germane to technical innovations in MC and related products. These are patents and PBR and thus exclude trade secrets, copyrights, franchises, or trademarks. Methods used for surveying the defined IPR landscape include searches of publicly available patent and PBR data and classifying the data according to the upstream–midstream–downstream innovation paradigm of the MC industry.
The findings suggest that the technical knowledge as expressed by patent filings is growing commensurate to the economic and legislative activity. Specific cannabis patents in agricultural technologies directed at improving yield, efficiency, and quality (known as “agritech”) are being filed and granted. These agritech-focused patents represent original novel and applied MC research achievements that address specific problems in cannabis cultivation, such as protection of the cannabis crop, maximizing cannabis yield, harvesting and post-harvesting of cannabis, and new advantageous varieties. Patents on ex planta and in planta cannabis genes expression have been published in recent years while patents on extraction methods for cannabinoids have increased since 2015. Much patent activity is in the downstream category of MC patient-oriented products and delivery systems for a very wide range of medical indications and disease conditions.
The emerging importance of access and benefit-sharing treaties and regulations is noted with implications on the industry briefly discussed. Patent data on leading and emerging patentee companies and institutions are shown. We also provide evidence of prior art and freedom to operate.
... 2-arachidonoylglycero exists in high levels in the brain, whereas Narachidonylethanolamine is primary being located in other parts of the human body. They are both agonists at CB1 and CB2 receptors [123,124]. The consumption of exogen cannabinoids such as THC or CBD enhances the productivity of the endocannabinoid system. ...
This review paper gives an overview of Cannabis Sativa, also known as hemp, which has been cultivated and used century's B.C. due to its medical, hallucinogenic and agricultural properties. Cannabis has been described in 1938 as the billion-dollar plant but has lost its value in the U.S. due to regulatory and legislative issues. Hemp has seen as new push In the U.S. with the introduction of the 2018 Farm Bill which allows on a federal level to grow hemp, pending on individual state regulations. Currently, industrial hemp production is allowed in at least 38 U.S. States under strict regulations. Today hemp is used in counties that do not have as strict regulations as the U.S. in a variety of applications such as beauty products, carpets, cooking oil, personal care products and textiles. Hemp can be considered as an alternative feedstock due to its low lignin and high cellulose level for biofuel application as an alternative to replace petroleum-based fuels and gases. In the U.S. hemp research in these areas has stalled due to the complexity of the law. Beside industrial application such as ropes, textiles, shoes, etc., hemp today is used in pharmaceutical and medical applications, by extracting Δ9-tetrahydrocannabinol and cannabinoids from the leaves and fluorescence of the hemp plant that contain no more than of up to 0.3% of these compounds. The use of hemp plants with higher levels are strictly forbidden in most countries. Several extraction processes of cannabinoids from hemp are used They all use a solvent for extraction but differ in terms of efficiency, usage range and other factors influencing the extraction. Nonetheless, overconsumption of cannabis products can be associated with several side effects, that can cause serious physiological and psychological damage in the human body may cause serious damage.
... Previous studies suggested that the ECS participates in immune control in the CNS [12], maintaining the overall 'fine-tuning' of immune homeostatic balance [13] and influencing neuroendocrine responses to inflammation and infection [14]. Thus, pharmacological modulation of CBR and/or the enzymes that control its synthesis, transport, and degradation is an option for the treatment of numerous neurological disorders [15], reinforcing the role of the ECS in neuroinflammatory conditions [16]. ...
Described during the late 1980s and 1990s, cannabinoid receptors (CB1R and CB2R) are G-protein-coupled receptors (GPCRs) activated by endogenous ligands and cannabinoid drug compounds, such as Δ9-THC. Whereas CB1R has a role in the regulation of neurotransmission in different brain regions and mainly mediates the psychoactive effects of cannabinoids, CB2R is found predominantly in the cells and tissues of the immune system and mediates anti-inflammatory and immunomodulatory processes. Studies have demonstrated that CB1R and CB2R can affect the activation of T cells, B cells, monocytes, and microglial cells, inhibiting proinflammatory cytokine expression and upregulating proresolution mediators. Thus, in this review, we summarize the mechanisms by which CBRs interact with the autoimmune environment and the potential to suppress the development and activation of autoreactive cells. Finally, we highlight how the modulation of CB1R and CB2R is advantageous in the treatment of autoimmune diseases, including multiple sclerosis (MS), type 1 diabetes mellitus (T1DM) and rheumatoid arthritis (RA).
... Many reviews from Cannabis have been published covering individual aspects on phytochemistry, pharmacology, ethnobotany, isolation and detection methods; among others (Brown 1998a;Small 2015). Although a few reviews about patents from some specialized topics have been published (Gerra et al. 2010;Ranieri et al. 2016), there are no reviews exploring different fields of patent applications from Cannabis specialized or secondary metabolism. As shown later, its specialized metabolism has been an immense source of isolation method development, synthesis, production, genes, improved plant varieties, and so on. ...
Specialized or secondary metabolism of plants from the genus Cannabis has been widely studied, generating a huge investment in research and development of patents. This review highlights the most recent patents granted so far, with some exceptions, covering different areas of knowledge including biotechnological aspects of plant specialized/secondary metabolism. Several patent databases were consulted in order to collect patent information. There are patents for specialized/secondary metabolite isolation methods, synthesis, production, genes, development of medicaments, drug delivery systems, equipment, machines, industrial processes, plant culture techniques, improved plant varieties, among others. Furthermore, important aspects such as nutrition and fiber production having unlimited applications in several areas are discussed. Endocannabinoid system is a special topic that has been included in this review due to interconnections among cannabinoids, endocannabinoids and its medical effects in human beings. This review of the state-of-the-art about Cannabis patents has the potential to be a valuable source of organized information for those researchers developing projects in many aspects related to this important natural resource.
... Globally, there is an increased interest in the use of medicinal cannabis to treat a variety of medical and psychiatric disorders [90]. Emerging data suggest the endocannabinoid system as a potential target to treat core PTSD symptoms [91,92]. ...
Introduction: A wide range of medications have been studied for posttraumatic stress disorder (PTSD) and a number are registered for this indication. Nevertheless, current pharmacotherapies are only partially effective in some patients, and are minimally effective in others. Thus novel treatment avenues need to be explored.
Areas covered: In considering novel pharmacological agents for the treatment of PTSD, this paper takes a translational approach. We outline how advances in our understanding of the underlying neurobiology of PTSD may inform the identification of potential new treatment targets, including glutamatergic, noradrenergic and opioid pathways.
Expert commentary: Continued investigation of the neural substrates and signalling pathways involved in responses to trauma may inform the development of novel treatment targets for future drug development for PTSD. However, the translation of preclinical findings to clinical practice is likely to be complex and gradual.
BACKGROUND AND OBJECTIVES
Since the relatively recent discovery of the endocannabinoid system (ECS) and its fundamental role in regulating other systems, the subject has aroused interest in all areas of health, including Dentistry. Among the possible uses and benefits of cannabinoids are their performance in pain and its predisposing or perpetuating factors, such as bruxism and sleep disorders. Although the literature is still scarce, the mechanisms of action and satisfactory results of cannabinoids and other cannabis derivatives in these situations already allow their safe prescription. The objective of this study was to verify the current evidence on the use of cannabis derivatives in orofacial pain (OFP), reviewing what is known, to date, about the ECS and the prospects for its use with support and criteria.
CONTENTS
This research carried out a brief review of the cannabis plant history, addressing issues such as prejudice, prohibitions and interests, as well as its therapeutic use. Then, a review on ECS and its mechanisms of interest in OFP was presented. Next, the products derived from the plant and their effects, indications, contraindications, adverse effects, drug interactions, peculiarities and perspectives were discussed.
CONCLUSION
The more knowledge is gained about the ECS and the therapeutic benefits of cannabis components and derivatives, the greater the conviction that a new therapeutic frontier has indeed emerged. The growing number of good outcomes, including cases of OFP, obtained through well-conducted studies, brings a mixture of satisfaction and excitement. No therapy will achieve good results if it does not start from an accurate diagnosis. Thus, it is of the utmost importance to know the ECS, the products and derivatives of the plant, the synthetic cannabinoids, their indications and effects. New studies are necessary and, at this moment, it can be said that the perspectives are very good and a new and challenging horizon is emerging.
Keywords:
Cannabidiol; Cannabis; Orofacial pain; Endocannabinoids; Dentistry
Cannabis sativa , also known as “hemp” or “weed,” is a versatile plant with various uses in medicine, agriculture, food, and cosmetics. This review attempts to evaluate the available literature on the ecology, chemical composition, phytochemistry, pharmacology, traditional uses, industrial uses, and toxicology of Cannabis sativa . So far, 566 chemical compounds have been isolated from Cannabis , including 125 cannabinoids and 198 non-cannabinoids. The psychoactive and physiologically active part of the plant is a cannabinoid, mostly found in the flowers, but also present in smaller amounts in the leaves, stems, and seeds. Of all phytochemicals, terpenes form the largest composition in the plant. Pharmacological evidence reveals that the plants contain cannabinoids which exhibit potential as antioxidants, antibacterial agents, anticancer agents, and anti-inflammatory agents. Furthermore, the compounds in the plants have reported applications in the food and cosmetic industries. Significantly, Cannabis cultivation has a minimal negative impact on the environment in terms of cultivation. Most of the studies focused on the chemical make-up, phytochemistry, and pharmacological effects, but not much is known about the toxic effects. Overall, the Cannabis plant has enormous potential for biological and industrial uses, as well as traditional and other medicinal uses. However, further research is necessary to fully understand and explore the uses and beneficial properties of Cannabis sativa .
Endocannabinoids are key intercellular signaling molecules in the brain, but the physiological regulation of the endocannabinoid system is not understood. We used the retrograde signal process called depolarization-induced suppression of inhibition (DSI) to study the regulation of this system. DSI is produced when an endocannabinoid released from pyramidal cells suppresses IPSCs by activating CB1R cannabinoid receptors located on inhibitory interneurons. We now report that activation of group I metabotropic glutamate receptors (mGluRs) enhances DSI and that this effect is blocked by antagonists of both mGluRs and of CB1R. We also found that DSI is absent in CB1R knock-out (CB1R(-/-)) mice, and, strikingly, that mGluR agonists have no effect on IPSCs in these mice. We conclude that group I mGluR-induced enhancement of DSI, and suppression of IPSCs, is actually mediated by endocannabinoids. This surprising result opens up new approaches to the investigation of cannabinoid actions in the brain.
Laboratory evidence has shown that cannabinoids might have a neuroprotective action. We investigated whether oral dronabinol (Δ(9)-tetrahydrocannabinol) might slow the course of progressive multiple sclerosis.
Delta(9)-tetrahydrocannabinol binds cannabinoid (CB(1) and CB(2)) receptors, which are activated by endogenous compounds (endocannabinoids) and are involved in a wide range of physiopathological processes (e.g. modulation of neurotransmitter release, regulation of pain perception, and of cardiovascular, gastrointestinal and liver functions). The well-known psychotropic effects of Delta(9)-tetra hydrocannabinol, which are mediated by activation of brain CB(1) receptors, have greatly limited its clinical use. However, the plant Cannabis contains many cannabinoids with weak or no psychoactivity that, therapeutically, might be more promising than Delta(9)-tetra hydrocannabinol. Here, we provide an overview of the recent pharmacological advances, novel mechanisms of action, and potential therapeutic applications of such non-psychotropic plant-derived cannabinoids. Special emphasis is given to cannabidiol, the possible applications of which have recently emerged in inflammation, diabetes, cancer, affective and neurodegenerative diseases, and to Delta(9)-tetrahydrocannabivarin, a novel CB(1) antagonist which exerts potentially useful actions in the treatment of epilepsy and obesity.
