ChapterLiterature Review

Cannabis Pharmacology: The Usual Suspects and a Few Promising Leads

Authors:
  • CReDO Science
  • Marcu & Arora
To read the full-text of this research, you can request a copy directly from the authors.

Abstract

The golden age of cannabis pharmacology began in the 1960s as Raphael Mechoulam and his colleagues in Israel isolated and synthesized cannabidiol, tetrahydrocannabinol, and other phytocannabinoids. Initially, THC garnered most research interest with sporadic attention to cannabidiol, which has only rekindled in the last 15 years through a demonstration of its remarkably versatile pharmacology and synergy with THC. Gradually a cognizance of the potential of other phytocannabinoids has developed. Contemporaneous assessment of cannabis pharmacology must be even far more inclusive. Medical and recreational consumers alike have long believed in unique attributes of certain cannabis chemovars despite their similarity in cannabinoid profiles. This has focused additional research on the pharmacological contributions of mono- and sesquiterpenoids to the effects of cannabis flower preparations. Investigation reveals these aromatic compounds to contribute modulatory and therapeutic roles in the cannabis entourage far beyond expectations considering their modest concentrations in the plant. Synergistic relationships of the terpenoids to cannabinoids will be highlighted and include many complementary roles to boost therapeutic efficacy in treatment of pain, psychiatric disorders, cancer, and numerous other areas. Additional parts of the cannabis plant provide a wide and distinct variety of other compounds of pharmacological interest, including the triterpenoid friedelin from the roots, canniprene from the fan leaves, cannabisin from seed coats, and cannflavin A from seed sprouts. This chapter will explore the unique attributes of these agents and demonstrate how cannabis may yet fulfil its potential as Mechoulam's professed “pharmacological treasure trove.”

No full-text available

Request Full-text Paper PDF

To read the full-text of this research,
you can request a copy directly from the authors.

... Over one hundred compounds with human protein receptor targets have been derived from the cannabis plant (Russo 2017). ...
... (−)-trans-Δ -tetrahydrocannabinol (THC) is one of the most widely studied cannabinoids, as it typically forms a heavy component of recreational cannabis use, and has pharmacological targets both within and outside the endocannabinoid system (Russo 2017). Dronabinol is a synthetic isomer of THC, and as a results, has similar chemical properties (Russo 2017). ...
... (−)-trans-Δ -tetrahydrocannabinol (THC) is one of the most widely studied cannabinoids, as it typically forms a heavy component of recreational cannabis use, and has pharmacological targets both within and outside the endocannabinoid system (Russo 2017). Dronabinol is a synthetic isomer of THC, and as a results, has similar chemical properties (Russo 2017). ...
Article
This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To assess the efficacy and safety of cannabis‐based medicines, compared to placebo or an alternative treatment strategy, for preventing nausea and vomiting during the postoperative period among adults undergoing elective surgery.
... Camphene is a bicyclic monoterpene commonly found in the essential oils of conifers, but also present in other plants (e.g., hemp, rosemary, pepper and nutmeg) [80][81][82][83]. This bioactive compound has been found to have hypolipidemic and weak antinociceptive properties. ...
... This bioactive compound has been found to have hypolipidemic and weak antinociceptive properties. It also acted as a spasmolytic agent in an experimentally induced bronchospasms in animals [80]. The anti-cancer properties of camphene were studied by Girola et al. on B16F10-Nex2 murine melanoma cell line and in vivo, in a syngeneic mouse model. ...
... It was proved to have antibacterial, anti-inflammatory and anticancer properties [92,93]. The latter were studied in breast and colon cancer models [80,92]. The anti-melanoma effect of limonene was investigated by Alipanah et al. on A375 cell line. ...
Article
Full-text available
Melanoma is responsible for the highest number of skin cancer-caused deaths worldwide. Despite the numerous melanoma-treating options, the fight against it remains challenging, mainly due to its great heterogeneity and plasticity, as well as the high toxicity of standard drugs. Plant-derived terpenoids are a group of plant defense molecules that have been proven effective in killing many different types of cancer cells, both in in vitro experiments and in vivo models. In this review, we focus on recent results in the search for plant terpenoids with anti-melanoma activity. We also report on the synergistic action of combining terpenoids with other plant-derived substances, MAP kinase inhibitors, or radiation. Additionally, we present examples of terpenoid-loaded nanoparticle carriers as anti-melanoma agents that have increased permeation through the cancer tissue.
... The first ones isolated in 1975 (examples: dehydrocannabifuran DCBF-C5, cannabifuran CBF-C5) [23] The discovery of these compounds led to the identification of cannabinoid receptors (CB1 and CB2) and endogenous ligands of the endocannabinoid system. There is evidence that this system plays an essential role in many normal physiological processes, such as memory, cognition, learning, motor control, anxiety, appetite, sleep, lipogenesis, fertility, formation of insulin and muscle fibers, vasomotricity, intestinal and bronchial motility, and immune modulation, but also in pathological-like pain, inflammation, and cancer [24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42]. ...
... However, an increasing amount of data sug-The discovery of these compounds led to the identification of cannabinoid receptors (CB1 and CB2) and endogenous ligands of the endocannabinoid system. There is evidence that this system plays an essential role in many normal physiological processes, such as memory, cognition, learning, motor control, anxiety, appetite, sleep, lipogenesis, fertility, formation of insulin and muscle fibers, vasomotricity, intestinal and bronchial motility, and immune modulation, but also in pathological-like pain, inflammation, and cancer [24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42]. ...
... The CBD acidic precursor cannabidiolic acid (CBDA) is one of the most present phytocannabinoids in European hemp [32]. Of all cannabinoid acids, CBDA seems to be the one with the weakest pharmacological activity, being studied thus far for its effects in pain, inflammation, and nausea but also for its therapeutic potential in treating breast cancer and in relieving the symptoms of Dravet syndrome [92,94,135,136]. ...
Article
Full-text available
The most important discoveries in pharmacology, such as certain classes of analgesics or chemotherapeutics, started from natural extracts which have been found to have effects in traditional medicine. Cannabis, traditionally used in Asia for the treatment of pain, nausea, spasms, sleep, depression, and low appetite, is still a good candidate for the development of new compounds. If initially all attention was directed to the endocannabinoid system, recent studies suggest that many of the clinically proven effects are based on an intrinsic chain of mechanisms that do not necessarily involve only cannabinoid receptors. Recent research has shown that major phytocannabinoids and their derivatives also interact with non-cannabinoid receptors such as vanilloid receptor 1, transient receptor ankyrin 1 potential, peroxisome proliferator-activated receptor-gamma or glitazone receptor, G55 protein-coupled receptor, and nuclear receptor, producing pharmacological effects in diseases such as Alzheimer’s, epilepsy, depression, neuropathic pain, cancer, and diabetes. Nonetheless, further studies are needed to elucidate the precise mechanisms of these compounds. Structure modulation of phytocannabinoids, in order to improve pharmacological effects, should not be limited to the exploration of cannabinoid receptors, and it should target other courses of action discovered through recent research.
... Conversely, an emphasis will be placed on the isolation and characterization techniques from 1970 to 2021 to have a broadened view of the advancements in analytical techniques over the past years. Overall, twenty-nine (29) papers relating to the areas of our focus were chosen and were reviewed by all authors. The results from the search were carefully sorted, based on a general understanding, the review questions, and the related objectives. ...
... Tetrahydrocannabinol THC Antioxidant, anti-pruritic, and anti-inflammatory effects [29,100] Cannabidiol CBD Anti-convulsive, anti-inflammatory, immunosuppressive properties, antioxidant, and anti-psychotic effects [101][102][103] Cannabigerol CBG Anti-fungal effects, anti-cancer, anti-depressant, mild anti-hypertensive agent, analgesic, and antierythemic effects [29,104] Cannabichromene CBC Anti-inflammatory and analgesic [29] Cannabinol CBN Sedative, anti-convulsant, anti-inflammatory, antibiotic, and anti-MRSA activity [29] Tetrahydrocannabivarin THCV Anti-convulsant [29] Tetrahydrocannabinolic acid THCA Immunomodulatory, anti-inflammatory, neuroprotective, anti-neoplastic activity, and antiemetic effects [29,105] Cannabidavarin CBDV Anti-convulsant (anti-epileptic) properties and anti-emetic properties [106,107] Cannabidiolic acid CBDA Anti-emetic effects [104,[108][109][110] β-Myrcene Anti-inflammatory and analgesic sedative agent [7,29,111] ...
... Tetrahydrocannabinol THC Antioxidant, anti-pruritic, and anti-inflammatory effects [29,100] Cannabidiol CBD Anti-convulsive, anti-inflammatory, immunosuppressive properties, antioxidant, and anti-psychotic effects [101][102][103] Cannabigerol CBG Anti-fungal effects, anti-cancer, anti-depressant, mild anti-hypertensive agent, analgesic, and antierythemic effects [29,104] Cannabichromene CBC Anti-inflammatory and analgesic [29] Cannabinol CBN Sedative, anti-convulsant, anti-inflammatory, antibiotic, and anti-MRSA activity [29] Tetrahydrocannabivarin THCV Anti-convulsant [29] Tetrahydrocannabinolic acid THCA Immunomodulatory, anti-inflammatory, neuroprotective, anti-neoplastic activity, and antiemetic effects [29,105] Cannabidavarin CBDV Anti-convulsant (anti-epileptic) properties and anti-emetic properties [106,107] Cannabidiolic acid CBDA Anti-emetic effects [104,[108][109][110] β-Myrcene Anti-inflammatory and analgesic sedative agent [7,29,111] ...
Article
Full-text available
Cannabis sativa is known among many cultures for its medicinal potential. Its complexity contributes to the historical application of various parts of the plant in ethno-medicines and pharmacotherapy. C. sativa has been used for the treatment of rheumatism, epilepsy, asthma, skin burns, pain, the management of sexually transmitted diseases, difficulties during child labor, postpartum hemorrhage, and gastrointestinal activity. However, the use of C. sativa is still limited, and it is illegal in most countries. Thus, this review aims to highlight the biological potential of the plant parts, as well as the techniques for the extraction, isolation, and characterization of C. sativa compounds. The plant produces a unique class of terpenophenolic compounds, called cannabinoids, as well as non-cannabinoid compounds. The exhaustive profiling of bioactive compounds and the chemical characterization and analysis of C. sativa compounds, which modern research has not yet fully achieved, is needed for the consistency, standardization, and the justified application of Cannabis sativa products for therapeutic purposes. Studies on the clinical relevance and applications of cannabinoids and non-cannabinoid phenols in the prevention and treatment of life-threatening diseases is indeed significant. Furthermore, psychoactive cannabinoids, when chemically standardized and administered under medical supervision, can be the legal answer to the use of C. sativa.
... Since their discovery, THC and CBD remain the two most studied phytocannabinoids for therapeutic application. THC is majorly associated with the modulation of pain-related stimuli, sedation, appetite and mood, besides action as bronchodilator and antioxidant with neuroprotective and anti-inflammatory potential (Williams et al., 1976;Russo and Marcu, 2017). THC agonist activity on CB1 induces four behavioral traits underlying its psychotropic effect in animal models, known as cannabinoid tetrad: hypolocomotion, hypothermia, catalepsy, and antinociception, while its action on CB2 is correlated with anti-inflammatory properties and pain relief (Russo and Marcu, 2017). ...
... THC is majorly associated with the modulation of pain-related stimuli, sedation, appetite and mood, besides action as bronchodilator and antioxidant with neuroprotective and anti-inflammatory potential (Williams et al., 1976;Russo and Marcu, 2017). THC agonist activity on CB1 induces four behavioral traits underlying its psychotropic effect in animal models, known as cannabinoid tetrad: hypolocomotion, hypothermia, catalepsy, and antinociception, while its action on CB2 is correlated with anti-inflammatory properties and pain relief (Russo and Marcu, 2017). Even though CBD is not a direct agonist of cannabinoid receptors and acts as a negative allosteric modulator of CB1, the absence of psychotropic effect following its administration and its anti-inflammatory and immunosuppressive activity due to ECS modulation increases the possibility of medical application of this molecule in terms of several clinical conditions, from pediatric to adult patients (Di Marzo and Piscitelli, 2015;Russo and Marcu, 2017;Sampson, 2021). ...
... THC agonist activity on CB1 induces four behavioral traits underlying its psychotropic effect in animal models, known as cannabinoid tetrad: hypolocomotion, hypothermia, catalepsy, and antinociception, while its action on CB2 is correlated with anti-inflammatory properties and pain relief (Russo and Marcu, 2017). Even though CBD is not a direct agonist of cannabinoid receptors and acts as a negative allosteric modulator of CB1, the absence of psychotropic effect following its administration and its anti-inflammatory and immunosuppressive activity due to ECS modulation increases the possibility of medical application of this molecule in terms of several clinical conditions, from pediatric to adult patients (Di Marzo and Piscitelli, 2015;Russo and Marcu, 2017;Sampson, 2021). ...
Article
Full-text available
Historically, Cannabis is one of the first plants to be domesticated and used in medicine, though only in the last years the amount of Cannabis-based products or medicines has increased worldwide. Previous preclinical studies and few published clinical trials have demonstrated the efficacy and safety of Cannabis-based medicines in humans. Indeed, Cannabis-related medicines are used to treat multiple pathological conditions, including neurodegenerative disorders. In clinical practice, Cannabis products have already been introduced to treatment regimens of Alzheimer’s disease, Parkinson’s disease and Multiple Sclerosis’s patients, and the mechanisms of action behind the reported improvement in the clinical outcome and disease progression are associated with their anti-inflammatory, immunosuppressive, antioxidant, and neuroprotective properties, due to the modulation of the endocannabinoid system. In this review, we describe the role played by the endocannabinoid system in the physiopathology of Alzheimer, Parkinson, and Multiple Sclerosis, mainly at the neuroimmunological level. We also discuss the evidence for the correlation between phytocannabinoids and their therapeutic effects in these disorders, thus describing the main clinical studies carried out so far on the therapeutic performance of Cannabis-based medicines.
... Terpenes are a family of organic compounds which biosynthetically produced by isoprene units found mainly in plants. Certain cannabis terpenes have been identified and studied in plants such as tea tree, lavender, thyme, basil, Pinus sp., frankincense and citrus fruits like lemon and mandarin (Russo & Marcu 2017;Del Prado-Audelo ML et al., 2021). Monoterpenes and sesquiterpenes of cannabis (the volatile compounds) mainly exist in the essential oil which is isolated by hydrodistillation (Radwan et al., 2021). ...
... Monoterpenes and sesquiterpenes of cannabis (the volatile compounds) mainly exist in the essential oil which is isolated by hydrodistillation (Radwan et al., 2021). Among terpenes, the monoterpene; β-myrcene is mentioned to have the highest prevalence in modern cannabis chemovars in the US (Russo & Marcu 2017). The Sixteen commonly encountered monoterpenes from three classes (acyclic, monocyclic and bicyclic monoterpenes) are shown ( Figure 2). ...
... Sesquiterpenes have a 15-carbon skeleton. The most abundant sesquiterpenes of cannabis are drawn ( Figure 3) (Russo & Marcu 2017). Other sources cite additional terpenes as most predominant based on samples from more specific geographic locations (Fischedick, 2017;Radwan 2021). ...
Article
Full-text available
“Hemp” refers to non-intoxicating, low delta-9 tetrahydrocannabinol (Δ9-THC) cultivars of Cannabis sativa L. “Marijuana” refers to cultivars with high levels of Δ9-THC, the primary psychoactive cannabinoid found in the plant and a federally controlled substance used for both recreational and therapeutic purposes. Although marijuana and hemp belong to the same genus and species, they differ in terms of chemical and genetic composition, production practices, product uses, and regulatory status. Hemp seed and hemp seed oil have been shown to have valuable nutritional capacity. Cannabidiol (CBD), a non-intoxicating phytocannabinoid with a wide therapeutic index and acceptable side effect profile, has demonstrated high medicinal potential in some conditions. Several countries and states have facilitated the use of THC-dominant medical cannabis for certain conditions, while other countries continue to ban all forms of cannabis regardless of cannabinoid profile or low psychoactive potential. Today, differentiating between hemp and marijuana in the laboratory is no longer a difficult process. Certain thin layer chromatography (TLC) methods can rapidly screen for cannabinoids, and several gas and liquid chromatography techniques have been developed for precise quantification of phytocannabinoids in plant extracts and biological samples. Geographic regulations and testing guidelines for cannabis continue to evolve. As they are improved and clarified, we can better employ the appropriate applications of this uniquely versatile plant from an informed scientific perspective.
... Though, the oil showed in vitro cytotoxic activity against MCF-7 human breast tumor cell line with 80± 5% kill at 100 μg/mL. This could be due to the presence of α-eudesmol, which has been reported to produce a cytotoxic effect in human hepatocellular carcinoma [132]. In addition to the in vitro cytotoxic activity, the oil was also slightly active in the brine shrimp lethality test with an LC 50 of 50 μg/mL. ...
... α-Pinene is bicyclic monoterpene [132] which is found in most of the Ficus species discussed in this review has myriads of medical usefulness. α-Pinene is made up of two enantiomers, the (−)-α-pinene and (+)-α-pinene, of which the positive enantiomer was found to possess antimicrobial activity [135]. ...
... α-Pinene is made up of two enantiomers, the (−)-α-pinene and (+)-α-pinene, of which the positive enantiomer was found to possess antimicrobial activity [135]. It is known to have high potency as an anti-bacterial agent [16], although it's highly effective against yeasts and a group of bacteria classified as Gram-positive [132,172]. α-Pinene's ability to work against bacteria is by inducing toxicity on the membrane structure, thus hampering the function of the membrane [198], and Table 1 presents pinene as one of the hydrocarbons in essential oils with antibacterial and antiviral as some of the potential activities. ...
Article
Full-text available
Compounds useful for drugs, cosmetics, and food have been obtained directly or indirectly from living organisms over the years. However, there has been a renewed interest in getting useful compounds from living organisms, especially plants. Essential oils, interchangeably called volatile oils, are bioactive compounds found in minute quantities in some plants. Essential or volatile oils have been known for years to find usefulness in foods, drugs (antimicrobial, antifungal), and cosmetics. This review attempts to summarize information on the essential oil from Ficus species concerning their morphology, pharmacology, bioactivity, and application. This was achieved by gathering information on essential oils from different Ficus species. Essential oils from Ficus species are a good source of bioactive compounds for use in drug, food, and cosmetic industries. It is worthy to note that Nigerian Figs were characterized by the high presence of phytol and 6,10,14-trimethyl-2-pentadecanone, and these compounds are, therefore, seen as markers. Furthermore, this review presents numerous insights on how to best harness the different potentials of the essential oils and possibilities to be examined.
... Cannabis sativa has been used for medical, recreational, and spiritual purposes for thousands of years (Russo, 2007). Modern scientific studies have provided increasing amounts of preclinical and clinical evidence about its beneficial pharmacological effects, including pain relief (Koppel et al., 2014;Russo and Marcu, 2017). Recent changes in the legislation of cannabis usage and possession have resulted in cannabis-based products becoming widely used alternatives in fighting against many different illnesses (Schmitz and Richert, 2020). ...
... Naturally occurring terpenes, including those in C. sativa, number in the hundreds, yet most of their pharmacology and signaling properties are poorly understood. Cannabis terpenes are reported to nonselectively target several G-protein-coupled receptors (GPCRs) (e.g., opioid receptors, CB1/2 receptors, G-proteincoupled receptor 55, dopamine, muscarinic, adrenergic, adenosine, etc.) and ion channels [e.g., transient receptor potential (TRPs), N-methyl-D-aspartate (NMDA), a-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA), kainate, nicotinic, potassium] to exert their pharmacological activities [summarized in Fig. 2; for a full review, see Russo and Marcu (2017)]. Although multiple receptor types can be implicated, terpenes can activate anti-or proinflammatory pathways that can contribute to or reduce synaptic relay of nociceptive transmission (Russo and Marcu, 2017). ...
... Cannabis terpenes are reported to nonselectively target several G-protein-coupled receptors (GPCRs) (e.g., opioid receptors, CB1/2 receptors, G-proteincoupled receptor 55, dopamine, muscarinic, adrenergic, adenosine, etc.) and ion channels [e.g., transient receptor potential (TRPs), N-methyl-D-aspartate (NMDA), a-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA), kainate, nicotinic, potassium] to exert their pharmacological activities [summarized in Fig. 2; for a full review, see Russo and Marcu (2017)]. Although multiple receptor types can be implicated, terpenes can activate anti-or proinflammatory pathways that can contribute to or reduce synaptic relay of nociceptive transmission (Russo and Marcu, 2017). Given the importance of target identification for understanding therapeutic efficacy, and reports of terpene-mediated relief in preclinical pain models, this section discusses known and recently identified molecular targets, preclinical studies, structure-activity relationships, and pharmacology of frequently observed cannabis monoterpenes and sesquiterpenes. ...
Article
Full-text available
Pain prevalence among adults in the United States has increased 25% over the past two decades, resulting in high health-care costs and impacts to patient quality of life. In the last 30 years, our understanding of pain circuits and (intra)cellular mechanisms has grown exponentially, but this understanding has not yet resulted in improved therapies. Options for pain management are limited. Many analgesics have poor efficacy and are accompanied by severe side effects such as addiction, resulting in a devastating opioid abuse and overdose epidemic. These problems have encouraged scientists to identify novel molecular targets and develop alternative pain therapeutics. Increasing preclinical and clinical evidence suggests that cannabis has several beneficial pharmacological activities, including pain relief. Cannabis sativa contains more than 500 chemical compounds, with two principle phytocannabinoids, Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD). Beyond phytocannabinoids, more than 150 terpenes have been identified in different cannabis chemovars. Although the predominant cannabinoids, Δ9-THC and CBD, are thought to be the primary medicinal compounds, terpenes including the monoterpenes β-myrcene, α-pinene, limonene, and linalool, as well as the sesquiterpenes β-caryophyllene and α-humulene may contribute to many pharmacological properties of cannabis, including anti-inflammatory and antinociceptive effects. The aim of this review is to summarize our current knowledge about terpene compounds in cannabis and to analyze the available scientific evidence for a role of cannabis-derived terpenes in modern pain management. SIGNIFICANCE STATEMENT: Decades of research have improved our knowledge of cannabis polypharmacy and contributing phytochemicals, including terpenes. Reform of the legal status for cannabis possession and increased availability (medicinal and recreational) have resulted in cannabis use to combat the increasing prevalence of pain and may help to address the opioid crisis. Better understanding of the pharmacological effects of cannabis and its active components, including terpenes, may assist in identifying new therapeutic approaches and optimizing the use of cannabis and/or terpenes as analgesic agents.
... Terpenoids are responsible for the fragrance and taste of the plant and are suggested to also have defensive roles. They also contribute to the therapeutic effects attributed to Cannabis (Russo and Marcu, 2017). Another group of metabolites worth mentioning is flavonoids. ...
... Therefore, it is likely that the content of secondary metabolites such as phytocannabinoids and terpenoids changes following the pollination and fertilization of Cannabis inflorescences. However, although mentioned in a few studies (Meier and Mediavilla, 1998;Potter, 2009;Russo and Marcu, 2017), this phenomenon was not studied in depth. In the last few years, an increasing number of Cannabis growers are moving from using cuttings from female "mother plants" to seeds. ...
Article
Full-text available
In the last decades, growing evidence showed the therapeutic capabilities of Cannabis plants. These capabilities were attributed to the specialized secondary metabolites stored in the glandular trichomes of female inflorescences, mainly phytocannabinoids and terpenoids. The accumulation of the metabolites in the flower is versatile and influenced by a largely unknown regulation system, attributed to genetic, developmental and environmental factors. As Cannabis is a dioecious plant, one main factor is fertilization after successful pollination. Fertilized flowers are considerably less potent, likely due to changes in the contents of phytocannabinoids and terpenoids; therefore, this study examined the effect of fertilization on metabolite composition by crossbreeding (-)-Δ ⁹ - trans -tetrahydrocannabinol (THC)- or cannabidiol (CBD)-rich female plants with different male plants: THC-rich, CBD-rich, or the original female plant induced to develop male pollen sacs. We used advanced analytical methods to assess the phytocannabinoids and terpenoids content, including a newly developed semi-quantitative analysis for terpenoids without analytical standards. We found that fertilization significantly decreased phytocannabinoids content. For terpenoids, the subgroup of monoterpenoids had similar trends to the phytocannabinoids, proposing both are commonly regulated in the plant. The sesquiterpenoids remained unchanged in the THC-rich female and had a trend of decrease in the CBD-rich female. Additionally, specific phytocannabinoids and terpenoids showed an uncommon increase in concentration followed by fertilization with particular male plants. Our results demonstrate that although the profile of phytocannabinoids and their relative ratios were kept, fertilization substantially decreased the concentration of nearly all phytocannabinoids in the plant regardless of the type of fertilizing male. Our findings may point to the functional roles of secondary metabolites in Cannabis .
... Myrcene is an alkene natural hydrocarbon acyclic monoterpene compound (C 10 H 16 : 7-Methyl-3-methylene-octa-1,6-diene) that exists in two isomers, the first of which is βmyrcene (the natural form), and the second form (α-myrcene) is not available naturally, but can be prepared industrially [42]. Myrcene is a colorless liquid found naturally in different sources (Supplementary Materials, Table S2) [38, [43][44][45]. ...
... Caryophyllene oxide (β-caryophyllene) is the oxidized form of caryophyllene (C 15 H 24 O: 1R, 4R, 6R, 10S-4, 12, 12-trimethyl-9-methylidene-5-oxatricyclo-8.2.0.0 (4,6)dodecane) with therapeutic applications [45]. There is a sesquiterpenoid compound called caryophyllene found in the essential oils of common eucalyptus Melaleuca stypheloides in concentrations as high as 43.8% [58]. ...
Article
Full-text available
The aquaculture sector is one of the main activities contributing to food security for humanity around the globe. However, aquatic animals are susceptible to several farming stressors involved in deteriorated growth performance, reduced productivity, and eventually high mortality rates. In some countries still, antibiotics and chemotherapies are comprehensively applied to control biotic stressors. Aside from the apparent benefits, the continuous usage of antibiotics develops bacterial resistance, deteriorates bacterial populations, and accumulates these compounds in the aquatic environment. Alternatively, environmentally friendly additives were used to avoid the direct and indirect impacts on the aquatic ecosystem and human health. In aquaculture, medicinal herbs and extracts are extensively used and approved for their growth-promoting, anti-inflammatory, and antioxidative properties. Herbal essential oils contain many bioactive components with powerful antibacterial, antioxidative, and immunostimulant potentials, suggesting their application for aquatic animals. Essential oils can be provided via diet and can benefit aquatic animals by improving their well-being and health status. The use of essential oils in aquafeed has been studied in a variety of aquatic animals to determine their beneficial roles and optimum doses. The outputs illustrated that herbal essential oils are exciting alternatives to antibiotics with prominent growth promotion, antioxidative, and immunostimulant roles. Herein, we reviewed the beneficial roles of essential oils in aquaculture. This review also aims to describe trends in herbal essential oils use, mainly in commercial fish species, and to analyze different factors that affect essential oils’ efficacy on the growth performance, antioxidative, and immune responses of finfish species.
... Terpenes are organic volatile compounds that, in the Cannabis plant, are synthesized alongside phytocannabinoids and accumulated in a resin in glandular trichomes, most of which is found on female inflorescences [13]. Their functions in the plant are fundamental for insect and herbivore repellence and pollinator attractance, and their presence is responsible for the plant's distinctive smell and flavor [14]. Their chemical structure is characterized by pairs of isoprene molecules and the amount of isoprene pairs determines if the terpene is mono, sesqui, di, etc., according to the number of carbons present in the molecule (10,15 or 20, respectively) [15]. ...
... Nutrients 2022,14, 468 ...
Article
Full-text available
The endocannabinoid system is a complex lipid signaling network that has evolved to be a key regulator of pro-homeostatic pathways for the organism. Its involvement in numerous processes has rendered it a very suitable target for pharmacological studies regarding metabolic syndrome, obesity and other lifestyle-related diseases. Cannabinomimetic molecules have been found in a large variety of foods, most of which are normally present in the Mediterranean diet. The majority of these compounds belong to the terpene and polyphenol classes. While it is known that they do not necessarily act directly on the cannabinoid receptors CB1 and CB2, their ability to regulate their expression levels has already been shown in some disease-related models, as well as their ability to modulate the activity of other components of the system. In this review, evidence was gathered to support the idea that phytocannabinoid dietary intake may indeed be a viable strategy for disease prevention and may be helpful in maintaining the health status. In an era where personalized nutrition is becoming more and more a reality, having new therapeutic targets could become an important resource.
... Cannabis (cannabis, hemp) plants have been used since millennial times as a rich source of food, fibers and oil as well as for medicinal, recreational or religious purposes [ 1 , 2 ]. Cannabis flowers are reported to contain a very complex phytochemical composition of at least 540 diverse metabolites, including more than 150 identified cannabinoids, such as 9 -tetrahydrocannabinol (THC) and cannabidiol (CBD), two of the most popular cannabinoids with incontestable pharmacological properties [3][4][5][6][7][8][9] . However, other cannabinoids, such as cannabigerol (CBG), cannabidivarin (CBDV), cannabinol (CBN) and cannabichromene (CBC), have been scarcely investigated [3] . ...
... Cannabis (cannabis, hemp) plants have been used since millennial times as a rich source of food, fibers and oil as well as for medicinal, recreational or religious purposes [ 1 , 2 ]. Cannabis flowers are reported to contain a very complex phytochemical composition of at least 540 diverse metabolites, including more than 150 identified cannabinoids, such as 9 -tetrahydrocannabinol (THC) and cannabidiol (CBD), two of the most popular cannabinoids with incontestable pharmacological properties [3][4][5][6][7][8][9] . However, other cannabinoids, such as cannabigerol (CBG), cannabidivarin (CBDV), cannabinol (CBN) and cannabichromene (CBC), have been scarcely investigated [3] . ...
Article
Aside from Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), other less common cannabinoids have recently gained an increasing popularity, mostly due to their promising biological potential. However, time-saving and cost-effective methods for their preparative purification are missing. In this study, trapping multiple dual mode (MDM), a flow-reversal liquid-liquid chromatography (LLC) operating mode, was used for the separation of different minor cannabinoids from a hemp extract. Separation task specific biphasic solvent systems were selected for the purification of the target constituents, as follows: n-hexane/methanol/water 10/6.5/3.5 for cannabielsoin (CBE); n-hexane/methanol/water 10/7/3 for cannabidivarin (CBDV) and cannabigerol (CBG); n-hexane/methanol/water 10/8/2 for cannabinol (CBN) and n-hexane/methanol/water 10/9/1 for cannabichromene (CBC) and cannabicylol (CBL). For each separation task, the concentration of the hemp extract in the feed stream and mobile phase flow rate were selected by shake-flask and stationary phase retention experiments, respectively. For the determination of the trapping MDM operating parameters, the short-cut method was implemented and followed by equilibrium-cell model-based simulations. The trapping MDM allowed the separation of the targeted cannabinoids with purities of 93-99%, yields of 73-95%, solvent consumption 2-4-fold lower and productivities almost double than those obtained using batch separation.
... Cannabis contains many components that provide many benefits on different symptoms from diseases like Alzheimer's and Parkinson's. For Alzheimer's disease, the symptoms that can benefit from cannabinoid treatment include agitation, anxiety, psychosis, insomnia, anorexia, aggression, depression, and neuroprotection (Russo and Marcu 2017). For these symptoms, different components of the plant appear to help with different symptoms. ...
... For these symptoms, different components of the plant appear to help with different symptoms. An approach that includes nutrition, lifestyle, and cannabinoids as treatment may prove to be more preventative while also providing better treatments; the combined approach includes aerobic activity and probiotic diets and supplantation with cannabis extracts (Russo 2018;Fallon and Enig 2001;Russo and Marcu 2017). ...
Chapter
Bhanga (Cannabis) has been reported with numerous therapeutic, traditional, commercial, and sacred uses in India and across the globe. Its uses are deeply rooted in the cultural, social, and economic lives of the people. The inclusion of Cannabis under ‘Scheduled E1’ drugs in India restricts its use. However, being a crop of economic and medicinal importance, the pharmaceutical and various other sectors are showing much interest in the plant. The present review article delineates traditional, culinary, cosmetic, ritual, social, spiritual, recreational, economic, and therapeutic uses of Cannabis. The review illustrates various uses of Cannabis across the globe; noted from articles, publications, and books providing description of various parts, viz. leaves and seeds (Bhanga), flowering and fruiting tops (Ganja), resin (Charas), extract, tincture, and whole plant, stalks (Fibers). The review may be helpful to researchers, clinicians, and pharmaceutical companies to carry out further research for developing cost-effective healthcare options.
... Cannabis contains many components that provide many benefits on different symptoms from diseases like Alzheimer's and Parkinson's. For Alzheimer's disease, the symptoms that can benefit from cannabinoid treatment include agitation, anxiety, psychosis, insomnia, anorexia, aggression, depression, and neuroprotection (Russo and Marcu 2017). For these symptoms, different components of the plant appear to help with different symptoms. ...
... For these symptoms, different components of the plant appear to help with different symptoms. An approach that includes nutrition, lifestyle, and cannabinoids as treatment may prove to be more preventative while also providing better treatments; the combined approach includes aerobic activity and probiotic diets and supplantation with cannabis extracts (Russo 2018;Fallon and Enig 2001;Russo and Marcu 2017). ...
... The content of cannabinoids was found to be differently distributed in plant parts with the highest percentage in secretory cells inside glandular trichomes (up to 60 %), highly concentrated in unpollinated female flowers prior to senescence (up to 30 %), pollinated flowers (up to 13 %), leaves (0.05 %), and least in the stem (0.02 %). No cannabinoids have been found in the roots or seeds (Russo and Marcu, 2017) (Russo, 2011). The highest cannabinoid concentration (in % of dry weight plant material) can be found in the bracts of the flowers that contain abundant glandular trichomes (Turner et al., 1981). ...
... 3A and 3B. Information gathered from publications indicate that it is expected that cannabinoid ratios between isolated glandular trichomes and whole pollinated flowers is approximately 1:4 (Russo and Marcu, 2017) in favor of glandular trichomes. From our results, as shown by evidence in Figs. ...
... α-Eudesmol and β-eudesmol, two major SO compounds, showed higher values in white flower buds (2.04% and 3.66%, respectively) than in violet flower buds (0.43% and 0.91%, respectively). Previous studies have demonstrated that β-eudesmol has diverse pharmacological activities, such as anticancer and anti-inflammatory effects, as well as effects on the nervous system [27,28]. ...
Article
Full-text available
Magnolia flower buds are a source of herbal medicines with various active compounds. In this study, differences in the distribution and abundance of major essential oils, phenolic acids, and primary metabolites between white flower buds of Magnolia heptapeta and violet flower buds of Magnolia denudata var. purpurascens were characterised. A multivariate analysis revealed clear separation between the white and violet flower buds with respect to primary and secondary metabolites closely related to metabolic systems. White flower buds contained large amounts of monoterpene hydrocarbons (MH), phenolic acids, aromatic amino acids, and monosaccharides, related to the production of isoprenes, as MH precursors, and the activity of MH synthase. However, concentrations of β-myrcene, a major MH compound, were higher in violet flower buds than in white flower buds, possibly due to higher threonine levels and low acidic conditions induced by comparatively low levels of some organic acids. Moreover, levels of stress-related metabolites, such as oxygenated monoterpenes, proline, and glutamic acid, were higher in violet flower buds than in white flower buds. Our results support the feasibility of metabolic profiling for the identification of phytochemical differences and improve our understanding of the correlated biological pathways for primary and secondary metabolites.
... [2][3][4] Cannabis is the source of many plant cannabinoids, including tetrahydrocannabinol (THC) and cannabidiol (CBD). 5,6 THC is the primary psychoactive component that might be helpful with neuropathic pain and spasticity but may worsen mental health symptoms such as posttraumatic stress disorder (PTSD). 7,8 On the other hand, CBD has no intoxicating effects but has analgesic, anti-inflammatory, anti-anxiety, and anti-psychotic effects that might be helpful with insomnia. ...
Article
LAY SUMMARY This research explored the demographic, military service, and health characteristics associated with cannabis for medical purposes (CMP) reimbursements among Veterans Affairs Canada (VAC) clients and respondents of the Life After Service Survey 2016 (LASS). Of the initial number of indicators selected contained in LASS 2016 survey, some specific variables were significantly associated with CMP reimbursement, from which physical/mental health and well-being indicators, such as anxiety, posttraumatic stress disorder (PTSD), depression, bowel ulcer, traumatic brain injury, chronic pain, needing help with tasks, psychological distress, and having three of more conditions of the PTSD diagnosis, were positively associated with CMP. Moreover, unemployment, having low income (< $5,000), a difficult adjustment, being very dissatisfied with life, having low social support, a weak community belonging, and reporting high stress also increased the odds of being reimbursed. These results will help to identify a preliminary profile of VAC clients with higher need for CMP reimbursement.
... Over the last few years increased interest in cannabis-based products has been observed within the clinical pharmacology sector for its properties in reducing the frequency of convulsive seizures (Perucca, 2017;Russo & Marcu, 2017). Two patents filed in 2018 by Gw Pharma Ltd refer to methods of obtaining purified cannabinoid compounds from Cannabis. ...
Article
Epilepsy, a neurologic condition associated with recurring seizures, affects around 70 million people worldwide and it is responsible for health costs. The current drug therapies used for treating epilepsy have low efficacy and many adverse side effects. In addition, drug resistance can also be found. The association of these factors considerably compromises the patient's pharmacotherapy care. Therefore, natural plant-derived products are promising therapeutic alternatives in the search for new curative options to treat epileptic seizures. Thus, the search was carried out at the patents database in the world, Espacenet, in January 2021 and compiled plant species (extracts, essential oils and isolated plant compounds) with a potential effect on the seizure, published between 2015 and 2020. In recent years, researchers and pharmaceutical companies have developed several methods for obtaining extracts, essential oils and purification of natural compounds, which have proven to be effective for the treatment of epileptic seizures in pre-clinical animal models. These findings hold potential promising for the treatment of epilepsy, especially for the management of drug-resistant, however, these reports are in their early stages and further studies need to be done for these compounds to be marketed.
... Secondary metabolites are directed outward (e.g., polyphenolic curcuminoids in turmeric rhizomes), often as a defensive mechanism, protecting the plant from herbivores, insects, or pathogens; thus, their biosynthesis is context-specific and highly regulated but also variable (36,37). However, even for well-studied plants like turmeric, where curcuminoids have been identified as a primary bioactive principle and are used for extract standardization (4), so called entourage effects are possible (38), with bioactivity resulting from additive and synergistic effects of component parts. In the case of turmeric, ground rhizome-containing polyphenols (3% curcuminoids by weight), terpene-rich essential oils and polysaccharides-is used both in cooking and for preparation of traditional medical formulations (39), whereas the content of most US turmeric dietary supplements is limited to curcuminoids only (98% curcuminoids by weight) (4). ...
Article
Full-text available
Plant-derived compounds, without doubt, can have significant medicinal effects since many notable drugs in use today, such as morphine or taxol, were first isolated from botanical sources. When an isolated and purified phytochemical is developed as a pharmaceutical, the uniformity and appropriate use of the product are well defined. Less clear are the benefits and best use of plant-based dietary supplements or other formulations since these products, unlike traditional drugs, are chemically complex and variable in composition, even if derived from a single plant source. This perspective will summarize key points–including the premise of ethnobotanical and preclinical evidence, pharmacokinetics, metabolism, and safety–inherent and unique to the study of botanical dietary supplements to be considered when planning or evaluating botanical clinical trials. Market forces and regulatory frameworks also affect clinical trial design since in the United States, for example, botanical dietary supplements cannot be marketed for disease treatment and submission of information on safety or efficacy is not required. Specific challenges are thus readily apparent both for consumers comparing available products for purchase, as well as for commercially sponsored vs. independent researchers planning clinical trials to evaluate medicinal effects of botanicals. Turmeric dietary supplements, a top selling botanical in the United States and focus of over 400 clinical trials to date, will be used throughout to illustrate both the promise and pitfalls associated with the clinical evaluation of botanicals.
... This prohibition was initiated mainly due to the narcotic properties of the plant (Booth, 2005). The major compound biosynthesized in the plant of cannabis (cannabinoid) with psychoactive properties, hence the cannabinoid responsible for the narcotic properties of cannabis, is the Δ-9tetrahydrocannabinol, also known as THC (Russo and Marcu, 2017). Through the last decades though, research conducted on the medical and industrial applications of cannabis, mainly due to another cannabinoid known as Cannabidiol (or CBD), renowned the interest regarding this crop (Bilalis et al., 2019;Farinon et al., 2020). ...
Conference Paper
Full-text available
A greenhouse pot experiment was conducted in the Agricultural University of Athens in order to evaluate the effect of several greenhouse cover materials on the performance and yield of hemp. The experiment was set up in a completely randomized design (CRD) with five treatments/greenhouses (G1, G2, G3, G4/Control, and G5). Measurements included plant height, PAR (Photosynthetic Active Radiation), chlorophyll content, solar irradiance, soil and leaf temperature, and yield components (the number of buds, their weight, length, and compact index, CBD content, and CBD yield per plant). The results of the present study suggest that the different polyethylene cover films alter the environment within the greenhouse and thus, affect the agronomic characteristics and yield traits of hemp. G1 reported the best results as it increased soil temperature and PAR values by 11-16% and 50-110% respectively, compared to G4. Concurrently, the majority of the bud characteristics were significantly improved in G1. Even though further research should be conducted in order to define the most suitable films for greenhouse hemp production, our results indicate that the optical properties of the greenhouse cover materials affect its yield and should always be considered.
... It produces numerous chemical compounds, including phytocannabinoids (such as tetrahydrocannabinol or THC and cannabidiol or CBD), terpenes, flavonoids, and phenolic acids (Andre et al., 2016). These substances have anti-inflammatory, anticancer, and neuroprotective effects, among others (Russo & Marcu, 2017). Phytocannabinoids interact with cannabinoid receptors and generate their pharmacological effects on the organism (Hazzah et al., 2020;Patil et al., 2020). ...
Preprint
Full-text available
The Asian elephant (Elephas maximus) is one of the largest herbivore mammals in the world. A portion of the total elephant population is under human care, where health problems such as skin lesions and decreased appetite are reported. The objective of this study was to apply the therapeutic properties of cannabidiol (CBD) to aid treatment of palmar abscesses and a suboptimal food intake in a female Asian elephant in Mexico. A CBD-isolate compounded medication was administered orally at a dose of 0.05 mg/kg/day. CBD administration showed positive effects such as reduction in abscess size, decreased food selectivity, increased food intake, weight gain and increased mobility. More research in elephants is needed to understand their cannabinoid pharmacodynamics and pharmacokinetics and proposing a dosage range and therapeutic applications for this species.
... CBD administered without THC has been shown to reduce subjective anxiety in both animals and humans and is thought to produce a positive effect on conditions such as inflammation, diabetes, cancer, and neurodegenerative diseases (Maroon and Bost, 2018). CBN is only weakly psychoactive and appears to be formed primarily from the degradation of THC within the Cannabis plant itself (Russo and Marcu, 2017). ...
Article
Full-text available
The legalization of cannabis in many parts of the United States and other countries has led to a need for a more comprehensive understanding of cannabis constituents and their potential for drug-drug interactions. While (-)-trans-Δ⁹-tetrahydrocannabinol (THC), cannabidiol (CBD), and cannabinol (CBN) are the most abundant cannabinoids present in cannabis, THC metabolites are found in plasma at higher concentrations and for a longer duration than that of the parent cannabinoids. To understand the potential for drug-drug interactions, the inhibition potential of major cannabinoids and their metabolites on major hepatic cytochrome P450 (CYP) enzymes was examined. In vitro assays with CYP-overexpressing cell microsomes demonstrated that the major THC metabolites 11-hydroxy-∆9-tetra-hydrocannabinol (11-OH-THC) and 11-COO-Δ9-THC-glucuronide (THC-COO-Gluc) competitively inhibited several major CYP enzymes, including CYP2B6, CYP2C9, and CYP2D6 (apparent Ki,u values = 0.086 {plus minus} 0.066 µM and 0.90 {plus minus} 0.54 µM, 0.057 {plus minus} 0.044 µM and 2.1{plus minus} 0.81 µM, 0.15 {plus minus} 0.067 µM and 2.3 {plus minus} 0.54 µM, respectively). 11-nor-9-carboxy-Δ9- tetrahydrocannabinol (THC-COOH) exhibited no inhibitory activity against any CYP450 tested. THC competitively inhibited CYPs 1A2, 2B6, 2C9, and 2D6, CBD competitively inhibited CYPs 3A4, 2B6, 2C9, 2D6, and 2E1, and CBN competitively inhibited CYPs 2B6, 2C9, and 2E1. THC and CBD showed mixed-type inhibition for CYP2C19 and CYP1A2, respectively. These data suggest that cannabinoids and major THC metabolites are able to inhibit the activities of multiple CYP enzymes, and basic static modelling of these data suggest the possibility of pharmacokinetic interactions between these cannabinoids and xenobiotics extensively metabolized by CYP2B6, CYP2C9 and CYP2D6. Significance Statement Major cannabinoids and their metabolites found in the plasma of cannabis users inhibit several CYP enzymes, including CYP2B6, CYP2C9, and CYP2D6. This study is the first to show the inhibition potential of the most abundant plasma cannabinoid metabolite, THC-COO-Gluc, and suggests that circulating metabolites of cannabinoids play an essential role in CYP450 enzyme inhibition as well as drug-drug interactions.
... The Cannabis sativa L. plants produce more than 560 chemicals, including at least 144 cannabinoids and 200 terpenoids, as well as flavonoids and polyunsaturated fatty acids [15,33,34,42,63,67,72,73,[90][91][92][93][94][95][96][97][98][99][100][101][102][103][104][105][106][107]. The most common phytocannabinoids are ∆ 9 -tetrahy drocannabinol (∆ 9 -THC) and cannabidiol (CBD), which are the neutral homologs of tetrahydrocannabinolic acid (THCA) and cannabidiol acid (CBDA), respectively [108]. ...
Article
Full-text available
Antibiotic resistance has become an increasing challenge in the treatment of various infectious diseases, especially those associated with biofilm formation on biotic and abiotic materials. There is an urgent need for new treatment protocols that can also target biofilm-embedded bacteria. Many secondary metabolites of plants possess anti-bacterial activities, and especially the phytocannabinoids of the Cannabis sativa L. varieties have reached a renaissance and attracted much attention for their anti-microbial and anti-biofilm activities at concentrations below the cytotoxic threshold on normal mammalian cells. Accordingly, many synthetic cannabinoids have been designed with the intention to increase the specificity and selectivity of the compounds. The structurally unrelated endocannabinoids have also been found to have anti-microbial and anti-biofilm activities. Recent data suggest for a mutual communication between the endocannabinoid system and the gut microbiota. The present review focuses on the anti-microbial activities of phytocannabinoids and endocannabinoids integrated with some selected issues of their many physiological and pharmacological activities.
... Of the 40 measured terpenes and cannabinoids, 12 (30%) were correlated with the Sativa-Indica scale at P < 0.01 ( Fig. 2a and Supplementary Fig. 1). Sativa content was positively correlated with the concentrations of bergamotene (R 2 = 0.12, P = 9.26 × 10 −8 ) and farnesene (R 2 = 0.11, P = 1.09 × 10 −7 ), which impart tea-like and fruity aromas, respectively 22,23 . This is consistent with descriptions of Sativa cultivars as having a 'sweet' or 'herbal' aroma 4,9 . ...
Article
Full-text available
Analysis of over 100 Cannabis samples quantified for terpene and cannabinoid content and genotyped for over 100,000 single nucleotide polymorphisms indicated that Sativa- and Indica-labelled samples were genetically indistinct on a genome-wide scale. Instead, we found that Cannabis labelling was associated with variation in a small number of terpenes whose concentrations are controlled by genetic variation at tandem arrays of terpene synthase genes. By quantifying over 100 Cannabis samples for terpene and cannabinoid content and genotyping them for over 100,000 single nucleotide polymorphisms, this study finds that Cannabis labelling is associated with genetic variants in terpene synthase genes.
... The bound antibody was detected using HRPconjugated anti-human kappa antibody. The plant-produced mAb provided higher binding affinity to Δ9-THC than CBN, which is the nonenzymatic oxidation byproduct of Δ9-THC [43]. In contrast, the plant-produced mAb showed no binding activity to other cannabinoid reference standards, including CBD, THCA and CBDA. ...
Article
Full-text available
Δ-9-tetrahydrocannabinol (Δ9-THC) is mainly a psychoactive compound in the cannabis plant. The immunoassay, an alternative method to HPLC and GC, can be used to analyze and measure Δ9-THC. This method provides high sensitivity and specificity by using antibodies specific to the desired substances. Currently, plants provide several benefits over traditional expression platforms to produce recombinant antibodies, such as lower production costs and scalability. Therefore, this study aims to produce a recombinant anti-Δ9-THC monoclonal antibody (mAb) with transient expression using N. benthamiana. The highest expression level of the plant-produced mAb was estimated to be 0.33 ug/g leaf fresh weight. Our results demonstrate that the antibody provided in vitro affinity binding related to Δ9-THC and the metabolites of Δ9-THC, such as cannabinol (CBN). Moreover, the antibody also showed binding efficiency with Δ9-THC in cannabis extract. Moreover, plant-produced mAbs provide efficiency against Δ9-THC and can be applied for further immunoassay applications.
... In humans, the endocannabinoid system consists of genes encoding cannabinoid receptors (CBRs) for endogenously produced cannabinoids (endocannabinoids) such as anandamide (AEA) and 2-arachidonoylglycerol (2-AG) and the enzymes involved in their synthesis and degradation [23]. Cannabinoid receptors (CBRs) are membrane G-protein-coupled receptors [24][25][26]. The two most important CBRs are cannabinoid receptor type 1 (CB1) and cannabinoid receptor type 2 (CB2) [27]. ...
Article
Full-text available
Breast cancer is the most common malignancy in women worldwide. Sixty-five percent of breast cancers are estrogen and/or progesterone receptor positive. Estrogen receptor expression is a prognostic and predictive biomarker of response to endocrine therapy, which consists of the selective estrogen receptor modulator tamoxifen, aromatase inhibitors, and the selective estrogen receptor degrader fulvestrant. Cannabidiol is a phytocannabinoid that is emerging as a potential therapeutic agent. The aim of this study was to investigate the effect of cannabidiol on estrogen receptor-positive and estrogen receptor-negative representative breast cancer cell lines in combination with standard therapeutic agents used in clinical practice. To compare the effects of cannabidiol on breast cancer cell viability, cancer cell lines were exposed to increasing concentrations of cannabidiol. The effects of cannabidiol in combination with the endocrine therapeutics tamoxifen, fulvestrant, and the cyclin-dependent kinase inhibitor palbociclib on breast cancer cell viability were examined. We demonstrated that cannabidiol dose-dependently decreased the viability of all breast cancer cell lines independent of estrogen expression. The addition of cannabidiol to tamoxifen had an additive negative effect on cell viability in ER + T-47D. Cannabidiol did not attenuate the effect of standard treatment of hormone receptor-positive breast cancer with fulvestrant and palbociclib. In addition, cannabidiol did not attenuate the effect of standard treatment of triple-negative breast cancer and HER2-positive breast cancer cell lines with trastuzumab and cisplatin.
... This rationale is due to the discovery that cannabis terpenoids and minor phytocannabinoids exhibit therapeutic capacity in a variety of pathologies, including Frontiers in Pharmacology | www.frontiersin.org April 2022 | Volume 13 | Article 881810 epilepsy, neurodegenerative disease, and traumatic brain injuries (Russo & Marcu, 2017;Russo, 2018). ...
Article
Full-text available
Cannabinoids, including those found in cannabis, have shown promise as potential therapeutics for numerous health issues, including pathological pain and diseases that produce an impact on neurological processing and function. Thus, cannabis use for medicinal purposes has become accepted by a growing majority. However, clinical trials yielding satisfactory endpoints and unequivocal proof that medicinal cannabis should be considered a frontline therapeutic for most examined central nervous system indications remains largely elusive. Although cannabis contains over 100 + compounds, most preclinical and clinical research with well-controlled dosing and delivery methods utilize the various formulations of Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), the two most abundant compounds in cannabis. These controlled dosing and delivery methods are in stark contrast to most clinical studies using whole plant cannabis products, as few clinical studies using whole plant cannabis profile the exact composition, including percentages of all compounds present within the studied product. This review will examine both preclinical and clinical evidence that supports or refutes the therapeutic utility of medicinal cannabis for the treatment of pathological pain, neurodegeneration, substance use disorders, as well as anxiety-related disorders. We will predominately focus on purified THC and CBD, as well as other compounds isolated from cannabis for the aforementioned reasons but will also include discussion over those studies where whole plant cannabis has been used. In this review we also consider the current challenges associated with the advancement of medicinal cannabis and its derived potential therapeutics into clinical applications.
... THC and CBD in combination have a synergistic effect, and it is suggested that presence of other phytocannabinoids in whole plants may create an "entourage effect," which could explain why whole plants have greater effects than extracted or synthetic THC and/or CBD alone [53,54], although this is controversial [55]. Other molecules found in Cannabis plants, such as terpenoids [56,57] and flavonoids [58], have been observed to have anti-inflammatory and anti-arthritic properties in mouse models. ...
Article
Full-text available
Purpose of Review Changing attitudes about marijuana have led to an increase in use of medicinal marijuana, especially for painful chronic conditions. Patients ask rheumatologists for guidance on this topic. This review provides up-to-date information on the safety and efficacy of medicinal cannabis for rheumatic disease pain. Recent Findings The number of publications related to rheumatic disease and cannabis has increased, but recent literature skews heavily toward reviews vs primary research. Data supporting a role for cannabinoids in rheumatic disease continue to grow. Observational and survey studies show increased use of medicinal cannabis, both by people with rheumatic disease and the general population, and suggest that patients find these treatments beneficial. Prospective studies, however, including randomized controlled clinical trials, are rare and sorely needed. Summary As medicinal cannabis use for rheumatic diseases rises, despite lack of evidence, we review the sparse data available and provide tips for conversations about medicinal cannabis for rheumatologists.
... No cannabinoids have been found in the seeds and roots. [22,23] Other researchers reported no qualitative differences in cannabinoid spectrum between different plant parts; only quantitative differences have been reported. [24,25] In the middle of the 20th century, the cultivation of hemp was banned by governments as an illegal drug crop. ...
Article
Full-text available
Hemp (Cannabis sativa L.), belongs to the Cannabaceae family. It is very rich in chemical constituents, especially the cannabinoids which has not been reported in any other plant, and has broad pharmacological properties. Hemp as a multi‐purpose crop is a good source of fibers, seed, fixed and volatile oil. It is known that the cannabinoid content of hemp is related to genetic factors, as well as plant’s growth stages and environmental factors such as latitude, altitude, weather, particularly moisture availability and nutrient supply during the growing season. The present study was designed to produce hemp that contains allowable concentration of THC (<.3%) by comparing different varieties of hemp, different stages of plant growth, and different geographical locations where it was planted. To achieve this, seeds of two native populations from Iran (Fars and Yazd Provinces) and one foreign variety from France (Fedora17, as an industrial hemp cultivar) with its progenies (Fedora17‐2) were cultivated in 3 research fields (Gilan, Golestan and Alborz provinces) in Iran. The following plant materials were extracted with methanol/chloroform and analyzed by HPLC: foliage in the vegetative stage, inflorescent in the flowering stage, inflorescent of seeds in the seeding stage and the mature seed. The THC concentration of Fedora17 (Fed17) in all three geographical locations was found to be under 0.03% or even non‐detectable. Same result was also observed in its progenies (Fed17‐2), indicating stability of the trait in this cultivar. The THC concentration of the Yazd variety that was planted in Alborz and Gilan regions was less than 0.080% in all growth stages. The female flowers planted in Golestan, showed a THC concentration of 1.029% which was more than the allowed THC concentration of <.3%. The THC concentration in all growth stages of all of the different varieties planted varied from 0 to 1.392%. The above results indicates that the type of cannabinoid produced depends on the difference in genetic prosperities of the different seed types as well as the growth stage in which the plant material was extracted. On the other hand, the climate and the region in which the seeds were planted had little influence on the THC concentration.
... Practically, the injected volume was 0.5 ml of either solvent or compounds. As terpineol was used in the range from 50-200 mg/Kg in various studies (Russo, Marcu, 2017), we chose the 100 mg/Kg dose based on those experiments. ...
Article
Full-text available
Abstract Alzheimer’s disease (AD) is a neurological disorder in which the neuronal degeneration is associated with inflammatory processes and oxidative stress. Since alpha-terpineol was shown to possess antioxidant and anti-inflammatory effects, the administration of this compound was studied on a rat model of AD. To create this model, Aβ1-42 was injected into the hippocampus of male Wistar rats. Generated AD models were divided into simple AD models and AD models in which short-term immobilization stress was added. Preventive and therapeutic (post-AD induction) effects of alpha-terpineol consumption (100 mg/Kg) were subsequently investigated in AD models, which were compared with control groups. Biochemical factors (superoxide dismutase and malondialdehyde), histological manifestations (amyloid plaques and neuron counts) and possible memory impairment (shuttle-box experiment) were investigated in all groups. For the in vitro experiment, alpha-terpineol effect was checked on Aβ1-42 fibril formation. In preventive and therapeutic modes, alpha-terpineol consumption could improve neurogenesis and long-term memory while reducing amyloid plaque counts and ameliorating biochemical factors (higher levels of superoxide dismutase and malondialdehyde and reduced levels of MDA). In vitro, shorter fibrillar structures were formed in the presence of alpha-terpineol, which indicates an anti-amyloid effect for this compound. In conclusion, alpha-terpineol significantly counteracted AD consequences.
... Cannabinoid production by hemp can be affected by several biotic and abiotic factors such as sex ratio, plant maturity, ambient temperature, soil nutrient availability and ultraviolet light intensity (Hillig and Mahlberg, 2004;Pexová Kalinová et al., 2021). In our case, we can speculate that temperature and precipitation from June onwards mainly affect the fluctuation of CBD in plants at the flowering stage because: (i) CBD being derived from a transformation of the main cannabinoid, cannabigerol (CBG), its concentration is lower during the first vegetative stage (Fellermeier and Zenk, 1998); (ii) CBD is almost absent in hemp roots, present at low rates in hemp leaves and more concentrated in glandular trichomes located in flower brackets (Russo and Marcu, 2017;Turner et al., 1980); (iii) for the cultivars used in this study, CBD is at its highest during the flowering and maturity stages (Hammami et al., 2021). The current study revealed that CBD content in grain and dual-purpose cultivars is positively affected by either hot and wet conditions, in agreement with field studies of Bazzaz et al. (1975), or by dry and cold conditions, in agreement with Pexová Kalinová et al. (2021). ...
Article
The study of the impact of climate change on crop production requires the examination of cultivar adaptation and performance in response to interannual variability in climate and field conditions. A field test was carried out during four years in Eastern New Brunswick, Canada, to study grain yield, fiber yield and floral cannabidiol content of eight Canadian industrial hemp (Cannabis sativa L., Cannabaceae) cultivars. Hemp performance in terms of grain and fiber production varied greatly between the years. The spatial location of plants in the field was shown to affect the performance of cultivars in different ways for grain and fiber yield. Grain yield was the highest in hot and humid summers, the opposite was observed for cannabidiol content, while fiber production was the highest in cold and humid summers. Our results indicated that grain, fiber or cannabidiol production cannot all be optimized under the given set of climatic conditions and that hemp performance is more sensitive to interannual variability of climatic conditions and intra-field variability than to cultivar effects. Yet, despite the considerable spatiotemporal variability documented, some cultivars have repeatedly exhibited the best performance, demonstrating excellent adaptation to local field conditions.
... It has been isolated from both oak cork and leaves, and from a marine alga (Mollo et al. 2017 and references therein). Friedelin is also the most prominent triterpenoid in cannabis (Russo and Marcu 2017). Triterpenoids are often associated with taste perceptions and, given their high molecular weight and their extremely low solubility in water, need to be detected by touch in both terrestrial and aquatic environments within the situation described in D. ...
... Given the volume of a sphere as 4/3πr 3 , a 150 µ diameter capitate glandular trichome on the bract of a cannabis inflorescence would have a volume of 1.77 × 10 −3 mm 3 as compared to a 30 µ diameter sessile trichome on a leaf with a volume of 1.41 × 10 −5 mm 3 , which is a two order of magnitude difference. Additionally, sessile trichomes are qualitatively different biochemically, favoring bitter sesquiterpenes over monoterpenes to dissuade predatory grazing [1][2][3]. As such, cannabis flowers may contain phytocannabinoid concentrations 18-20 fold greater than the leaves [1]. ...
Article
Full-text available
Despite its use by humans for thousands of years, the technology of cannabis usage and extraction is still evolving. Given that the primary pharmacological compounds of interest are cannabinoid and terpenoids found in greatest abundance in capitate glandular trichomes of unfertilized female inflorescences, it is surprising that older techniques of hashish making have received less technological advancement. The purpose of this study was to employ organically grown cannabis and to isolate pure trichomes from freshly picked flowers via exposure to vapor from solid CO2, commonly known as “dry ice”, followed by their isolation via sifting through a 150 µ screens while maintaining the cold chain. Biochemical analysis was undertaken on fresh flower, frozen-sifted flower by-products, treated trichomes (Kryo-Kief™), dried flower, dried sifted flower by-product and dried kief. The dry ice process successfully concentrated cannabinoid content as high as 60.7%, with corresponding concentration and preservation of monoterpenoids encountered in fresh flower that are usually lost during the conventional cannabis drying and curing process. The resulting dried sifted flower by-product after dry ice processing remains a usable commodity. This approach may be of interest to pharmaceutical companies and supplement producers pursuing cannabis-based medicine development with an eye toward full synergy of ingredients harnessing the entourage effect.
... Otherwise, p-cymene and α-humelene (α-caryophyllene) are monoterpenes and sesquiterpenes, respectively. The compounds have demonstrated varying bioactivity as an adjunct against inflammatory, cancer, and microbial ailments [34,35]. Oliveira et al. [36] also conducted an in vivo study that demonstrated p-cymene potential against gastric lesions. ...
Article
Full-text available
Lippia graveolens is a traditional crop and a rich source of bioactive compounds with various properties (e.g., antioxidant, anti-inflammatory, antifungal, UV defense, anti-glycemic, and cytotoxicity) that is primarily cultivated for essential oil recovery. The isolated bioactive compounds could be useful as additives in the functional food, nutraceuticals, cosmetics, and pharmaceutical industries. Carvacrol, thymol, β-caryophyllene, and p-cymene are terpene compounds contained in oregano essential oil (OEO); flavonoids such as quercetin O-hexoside, pinocembrin, and galangin are flavonoids found in oregano extracts. Furthermore, thermoresistant compounds that remain in the plant matrix following a thermal process can be priced in terms of the circular economy. By using better and more selective extraction conditions, the bioactive compounds present in Mexican oregano can be studied as potential inhibitors of COVID-19. Also, research on extraction technologies should continue to ensure a higher quality of bioactive compounds while preventing an undesired chemical shift (e.g., hydrolysis). The oregano fractions can be used in the food, health, and agricultural industries.
... Actual plasma levels of active and inactive cannabinoids are highly variable (in the micromolar to sub-micromolar range) and will vary widely depending on the user, dose and method of ingestion. Cannabinol (CBN) appears to be a degradation product of THC within the Cannabis plant (Russo and Marcu, 2017) and has been shown to be only weakly psychoactive. Cannabidiol (CBD) is often termed as medical marijuana and interacts with the CB 1 and CB 2 receptors in the brain with a much lower affinity as compared to THC and 11-OH-THC, resulting in extremely low psychoactive effects (Pertwee, 2008). ...
Article
The UDP-glucuronosyltransferase (UGT) family of enzymes play a central role in the metabolism and detoxification of a wide range of endogenous and exogenous compounds. UGTs exhibit a high degree of structural similarity and display overlapping substrate specificity, often making estimations of potential drug-drug interactions difficult to fully elucidate. One such interaction yet to be examined may be occurring between UGTs and cannabinoids, as the legalization of recreational and medicinal cannabis and subsequent co-usage of cannabis and therapeutic drugs increases in the U.S. and internationally. In the present study, the inhibition potential of the major cannabinoids Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), and cannabinol (CBN), as well as their major metabolites, was determined in microsomes isolated from HEK293 cells over-expressing individual recombinant UGTs and in microsomes from human liver and kidney specimens. The highest inhibition was seen by CBD against the glucuronidation activity of UGTs 1A9, 2B4,1A6 and 2B7, with binding- corrected IC50,u values of 0.12 {plus minus} 0.020 µM, 0.22 {plus minus} 0.045 µM, 0.40 {plus minus} 0.10 µM and 0.82 {plus minus} 0.15 µM, respectively. Strong inhibition of UGT1A9 was also demonstrated by THC and CBN, with IC50,u values of 0.45 {plus minus} 0.12 µM and 0.51 {plus minus} 0.063 µM, respectively. Strong inhibition of UGT2B7 was also observed for THC and CBN; no or weak inhibition was observed with cannabinoid metabolites. This inhibition of UGT activity suggests that in addition to playing an important role in drug-drug interactions, cannabinoid exposure may have important implications in patients with impaired hepatic or kidney function.
... Caryophyllene oxide is reported in the EO from the genera Cinnamomum verum J.Presl, Syzygium aromaticum Merr. & L.M.Perry, M. officinalis, Zataria multiflora Boiss., and Eucaliptos [104][105][106]. The EO from Z. multiflora, with caryophyllene oxide in its composition, showed satisfactory antiviral action against HSV-1 [81], which was also observed for spathulenol, a majority compound in Eucalyptus polybractea F.Muell. ...
Article
Full-text available
Essential oils (EOs) and their compounds have attracted particular attention for their reported beneficial properties, especially their antiviral potential. However, data regarding their anti-SARS-CoV-2 potential are scarce in the literature. Thus, this study aimed to identify the most promising EO compounds against SARS-CoV-2 based on their physicochemical, pharmacokinetic, and toxicity properties. A systematic literature search retrieved 1669 articles; 40 met the eligibility criteria, and 35 were eligible for analysis. These studies resulted in 465 EO compounds evaluated against 11 human and/or SARS-CoV-2 target proteins. Ninety-four EO compounds and seven reference drugs were clustered by the highest predicted binding affinity. Furthermore, 41 EO compounds showed suitable drug-likeness and bioactivity score indices (≥0.67). Among these EO compounds, 15 were considered the most promising against SARS-CoV-2 with the ADME/T index ranging from 0.86 to 0.81. Some plant species were identified as EO potential sources with anti-SARS-CoV-2 activity, such as Melissa officinalis Arcang, Zataria multiflora Boiss, Eugenia brasiliensis Cambess, Zingiber zerumbet Triboun & K.Larsen, Cedrus libani A.Rich, and Vetiveria zizanoides Nash. Our work can help fill the gap in the literature and guide further in vitro and in vivo studies, intending to optimize the finding of effective EOs against COVID-19.
Chapter
Dementia is a group of diseases characterized by gradual impairment of brain function. Alzheimer’s disease is the most common form of dementia and is characterized by many neuropsychiatric symptoms, of which loss of memory is only one and possibly not the most problematic. The pathophysiology of Alzheimer’s disease involves a triad of neuroinflammation, formation of amyloid plaques, and hyperphosphorylation of tau protein. The endocannabinoid system is involved in the pathophysiology of Alzheimer’s disease and, because of this, may be an important therapeutic target in the future. Preclinical and clinical research indicates that cannabidiol, tetrahydrocannabinol, and some of terpenes found in cannabis may be useful in the treatment of the neurobehavioural aspects of the condition. Medicinal cannabis may be a valuable part of a holistic approach to the treatment of AD that considers a range of factors including diet, exercise, stress reduction, and others. This chapter explores the evidence that key phytocannabinoids such as cannabidiol and tetrahydrocannabinol and some of the other phytonutrients of Cannabis sativa may have a role to play in the treatment of this disease that, as yet, has no cure.
Article
Full-text available
Terpenes are fragrant aromatic compounds produced by a variety of plants, most notably cannabis and hops. With increasing legalization of cannabis there is a need to better understand the behavioural effects of terpenes and ultimately their therapeutic value. Our study investigated the dose-dependent impact of three terpenes (limonene 0.25, 0.5, 0.75%; β-myrcene 0.001, 0.01, 0.1%; and 0.0001, 0.001, 0.00125% linalool) on zebrafish (Danio rerio) behaviour when exposed both acutely and repeatedly over a 7-day period. Anxiety-like behaviour, boldness, and locomotion were assessed using the open field test and the novel object approach test. In the acute dosing experiment, limonene and β-myrcene exposed groups demonstrated a significant decrease in locomotion, a decrease in anxiety-like behaviour, and an increase in boldness, while linalool treatment groups demonstrated only minor alterations in locomotion. Moreover, repeated exposure to limonene (0.39%) or β-myrcene (0.0083%) for a seven day period did not result in any significant behavioural effects. In conclusion, our study provides support for an anxiolytic and sedative effect in zebrafish in response to acute limonene and β-myrcene exposure that is no longer present after one week of repeated exposure.
Article
Full-text available
Substance use disorder (SUD) is a global public health concern that affects millions of people worldwide. Considering current research, addiction has been noted as the last stage of a chronic disease that may impair brain reward circuit responses and affects personal and social life. Treatments for SUD face challenges including availability and limited pharmacological response, often resulting in low retention of patients. A growing number of studies from the 'psychedelic renaissance' have highlighted the therapeutic potential of psychedelics for several psychiatric disorders, including SUD. In this non-systematic review we discuss past and current clinical and observational studies with classic (LSD, DMT, psilocybin and mescaline) and non-classic (ibogaine, ketamine, MDMA, salvinorin A and THC) psychedelics for the treatment of SUD published until December 2021. Although results are still inconclusive for LSD, DMT, mescaline, MDMA and Salvinorin A, in general, the literature presents moderate evidence on the controlled use of psilocybin and ketamine for Alcohol Use Disorder, ketamine for management of opiate and alcohol withdrawal, and THC preparations for reducing withdrawal symptoms in Cannabis and possibly in Opioid Use Disorder. Importantly, studies suggest that psychedelics should be more effective when employed as an adjunct therapy. Extensive research is warranted to further elucidate the role of psychedelics in the treatment of SUD.
Article
Cannabis use in the United States is growing at an unprecedented pace. Most states in the United States have legalized medical cannabis use, and many have legalized nonmedical cannabis use. In this setting, health care professionals will increasingly see more patients who have questions about cannabis use, its utility for medical conditions, and the risks of its use. This narrative review provides an overview of the background, pharmacology, therapeutic use, and potential complications of cannabis.
Chapter
This two-part section helps the reader to achieve a better understanding of how cannabis works as a viable medication for the endocannabinoid system (ECS) and central nervous system (CNS) in humans by identifying individual synergies between cannabinoids, or cannabinoids and terpenes in their journey through the ECS and CNS in various mammalian patient indicators to unmask this paradoxical effect. The specific biphasic/paradoxical manner in question was researched and inevitably identifies cannabis use that manipulates tryptophan uptake, serotonin release, and dopamine actuation. Therefore, a patient’s diet may demand a higher tryptophan and dopa-L supplementation to avoid a paradoxical agitation on the receptor level. This chapter explains the pathology of how cannabis consistently reacts in the ECS for every individual, only separated by metabolism and disruption/trauma in the ECS and CNS, implying that there was no found paradoxical effect existing in cannabis, but in the patient, and thus is perceived the same in every individual, only mediated by metabolism, environment (surroundings), and the exception for individuals who process stimulants and tryptophan and/or serotonin in a disrupted manner causing a perceived paradoxical effect or the build-up to and/or what will be referred to as ASR/ATD. The cannabis industry, growers/breeders, interpeners/cannabis sommeliers/bud tenders, and dispensaries need to continue to constantly strive for more knowledge, just as the researchers and FDA need to continue their work to understand the benefits of cannabis, and most importantly, all must work together to remove cannabis from the Schedule I and Schedule 2 classification.
Article
Cannabis sativa (C. sativa) has become a worldwide plant because of its multiple bioactive compounds with a wide range of health benefits for humans. Notably, some cannabinoid-like compounds have also been found in other plant species besides C. sativa. However, efficient extraction, separation, purification, and identification technologies for bioactive compounds in C. sativa are still great challenges. This review provides an updated overview of the main bioactive compounds in C. sativa and the cannabinoid-like compounds in other plants. In addition, various advanced technologies for extracting, separating, purifying, and identifying the bioactive compounds in C. sativa are mainly summarized, compared, and discussed. Overall, this review can provide scientific basis and technical support for the efficient extraction, separation, purification, and identification of C. sativa bioactive compounds, which have the potential to be widely applied in the food, medical, nutraceutical, and beauty products.
Article
Full-text available
Recently, several studies have indicated an increased interest in the scientific community regarding the application of Cannabis sativa plants, and their extracts, for medicinal purposes. This plant of enormous medicinal potential has been legalised in an increasing number of countries globally. Due to the recent changes in therapeutic and recreational legislation, cannabis and cannabinoids are now frequently permitted for use in clinical settings. However, with their highly lipophilic features and very low aqueous solubility, cannabinoids are prone to degradation, specifically in solution, as they are light-, temperature-, and auto-oxidation-sensitive. Thus, plant-derived cannabinoids have been developed for oral, nasal-inhalation, intranasal, mucosal (sublingual and buccal), transcutaneous (transdermal), local (topical), and parenteral deliveries. Among these administrations routes, topical and transdermal products usually have a higher bioavailability rate with a prolonged steady-state plasma concentration. Additionally, these administrations have the potential to eliminate the psychotropic impacts of the drug by its diffusion into a nonreactive, dead stratum corneum. This modality avoids oral administration and, thus, the first-pass metabolism, leading to constant cannabinoid plasma levels. This review article investigates the practicality of delivering therapeutic cannabinoids via skin in accordance with existing literature.
Article
Medical cannabis products contain dozens of active pharmaceutical ingredients (APIs) derived from the cannabis plant. However, their actual compositions and relative doses significantly change according to the production methods. Product compositions are strongly dependent on processing step conditions and on components' evaporation during those steps. Review of the documentation presented to caregivers and to patients show erroneous data or misinterpretation of data related to the evaporation, for example, cannabinoids' boiling points, as well as confusions between terms, such as boiling, vaporization, and evaporation. Clarifying these aspects is essential for caregivers, for researchers, and for developers of manufacturing processes. Original and literature data were analyzed, comparing composition changes during various processing steps and correlating the extent of change to components' vapor pressures at the corresponding temperature. Evaporation-related composition changes start at temperatures as low as those of drying and curing and become extensive during decarboxylation. The relative rate of components' evaporation is determined by their relative vapor pressure and monoterpenes are lost first. On vaping, terpenes are inhaled before cannabinoids do. Commercial medical cannabis products are deficient in terpenes, mainly monoterpenes, compared with the cannabis plants used to produce them. Terms, such as "whole plant" and "full spectrum," are misleading since no product actually reflects the original cannabis plant composition. There are important implications for medical cannabis manufacturing and for the ability to make the most out of the terpene API contribution. Medical cannabis products' composition and product delivery are controlled by the relative vapor pressure of the various APIs. Quantitative data provided in this study can be used for improvement to reach better accuracy, reproducibility, and preferred medical cannabis compositions.
Article
Full-text available
Artemisia is one of the most diverse genera in the Asteraceae family. The genus is wildly distributed in Irano-Turanian habitats and includes 34 species in Iran. Here, for the first time the essential oil variability, antioxidants and anti-cholinesterase and anti-tyrosinase activities of extracts of three Artemisia species (A. tournefortiana, A. khorassanica, A. haussknechtii) , from different regions of Iran were evaluated. Based on GC–MS analyses, 81.84% to 98.70% of the total oils were identified. Cluster analysis grouped the studied populations in three different chemotypes. The highest and the lowest essential oil contents were observed in A. khorassanica and A. haussknechtii species, respectively. Camphor, en-in-dicycloether, 1,8-cineole and ( Z )- β -farnesene were the dominant components of essential oil in investigated ecotypes. The results revealed that the total phenol content was higher in A. tournefortiana collected from Kerman and A. haussknechtii collected from Chaharmahal and Bakhtiari. However, the lowest phenol content was recorded for A. haussknechtii collected from Isfahan province. The highest flavonoids content was found in A. tournefortiana collected from West Azerbaijan and A. khorassanica collected from North Khorasan. The highest FRAP antioxidant activity was observed in A. tournefortiana (Kerman) and the lower amount was in A. haussknechtii collected from Kohgiluyeh and Boyer-Ahmad. The highest antioxidant activity by DPPH method was in A. khorassanica collected from South Khorasan and the lowest activity was in Isfahan's A. haussknechtii. The acetycholine esterase inhibitory activity was higher in A. tournefortiana collected from West Azerbaijan; and the lowest activity was in A. haussknechtii collected from Chaharmahal and Bakhtiari province. The highest tyrosinase inhibitory activity was in A. khorassanica collected from North Khorasan; and the lowest was in A. haussknechtii collected from Chaharmahal and Bakhtiari.
Chapter
The application of medical marijuana is becoming increasingly widespread in the USA due, in part, to legalization in several states. The US federal government continues to categorize all forms of marijuana as illicit; however, the government has mainly not intervened with the applications of medical marijuana that have been deemed legitimate under state laws. Provided that peripheral neuropathy, neuropathic pain, and migraine are complicated conditions challenging to treat, this chapter reviews the effectiveness, roles, and consequences of medical marijuana in treating peripheral neuropathy and migraine. Furthermore, the study of the cannabinoid-mediated mechanisms in treating peripheral neuropathy and migraine is discussed.
Chapter
Plant-derived bioactive compounds have been extensively studied and used within food industry for the last few decades. Those compounds have been used to extend the shelf-life and improve physico-chemical and sensory properties on food products. They have also been used as nutraceuticals due to broad range of potential health-promoting properties. Unlike the synthetic additives, the natural plant-derived compounds are more acceptable and often regarded as safer by the consumers. This chapter summarizes the extraction methods and sources of those plant-derived bioactives as well as recent findings in relation to their health-promoting properties, including cardio-protective, anti-diabetic, anti-inflammatory, anti-carcinogenic, immuno-modulatory and neuro-protective properties. In addition, the impact of applying those plant-derived compounds on seafood products is also investigated by reviewing the recent studies on their use as anti-microbial, anti-oxidant, coloring and flavoring agents as well as freshness indicators. Moreover, the current limitations of the use of plant-derived bioactive compounds as well as future prospects are discussed. The discoveries show high potential of those compounds and the possibility to apply on many different seafood. The compounds can be applied as individual while more and more studies are showing synergetic effect when those compounds are used in combination providing new important research possibilities.
Article
Full-text available
Clinicians play an important role in promoting safe and responsible medical cannabis use. One essential component to safe use is considering a patient's risk of neurocognitive impairment. However, there remains a lack of practical guidance on how clinicians can evaluate this risk for medical cannabis patients. Here, a practical framework is presented for clinicians to assess and stratify cannabis-associated impairment risk. The proposed framework is intended to practically guide healthcare providers in gaining a more comprehensive review of a patient's impairment-related factors. This framework can be used to assess impairment risk for patients currently using or considering medical cannabis and is recommended for all patients who perform safety-sensitive duties. Healthcare providers (HCP) managing patient's medical cannabis or those conducting assessments to determine risk of impairment for safety-sensitive workplaces can utilize this framework to stratify patients' risk of impairment. Such assessments can inform patient-specific needs for support, education, and guidance, to ensure cannabis is used safely and responsibly.
Chapter
Here in part two, a brief explanation in essential oil/ terpene administration as well as cover the medicinal effects of terpenes focusing on biphasic pharmacokinetics and possible paradoxical reactions and molecular sites of interest, including the medicinal properties of a specific flavonoid; an explanation into the paradoxical entourage and identifying common misconceptions from cannabis use and education; we finalize our look into the paradoxical location learning biphasic and paradoxical reactions from cannabis with an in-depth look into the cause of ASR/ATD following with a fundamental explanation how stress with the wrong medication can instigate the situation. The Multi Cultivar Entourage Effect Chart (MCEEC) directed goal was to unravel multiple cultivars bioavailability to then combine and create a more robust and stronger entourage being pulled from multiple cultivars with specific bioavailability of cannabinoids, terpenoids, and flavonoids necessary to treat any specific indication. Indirectly the chart also identified inter-entourages, more importantly, “antagonistic” inter-entourages. By helping a patient describe their reactions, understand, identify and track terpenes and cannabinoids that cause specific reactions, the patient will be able to identify a profile that works for them, which gives an explanation and solution to identifying how to manage cannabis medication for the patient along with conclusion and thoughts.
Article
Full-text available
Cannabis (Cannabis sativa) plants produce and accumulate a terpene-rich resin in glandular trichomes, which are abundant on the surface of the female inflorescence. Bouquets of different monoterpenes and sesquiterpenes are important components of cannabis resin as they define some of the unique organoleptic properties and may also influence medicinal qualities of different cannabis strains and varieties. Transcriptome analysis of trichomes of the cannabis hemp variety 'Finola' revealed sequences of all stages of terpene biosynthesis. Nine cannabis terpene synthases (CsTPS) were identified in subfamilies TPS-a and TPS-b. Functional characterization identified mono-and sesqui-TPS, whose products collectively comprise most of the terpenes of 'Finola' resin, including major compounds such as β-myr-cene, (E)-β-ocimene, (-)-limonene, (+)-α-pinene, β-caryophyllene, and α-humulene. Transcripts associated with terpene biosynthesis are highly expressed in trichomes compared to non-resin producing tissues. Knowledge of the CsTPS gene family may offer opportunities for selection and improvement of terpene profiles of interest in different cannabis strains and varieties.
Article
Full-text available
Introduction: With laws changing around the world regarding the legal status of Cannabis sativa (cannabis) it is important to develop objective classification systems that help explain the chemical variation found among various cultivars. Currently cannabis cultivars are named using obscure and inconsistent nomenclature. Terpenoids, responsible for the aroma of cannabis, are a useful group of compounds for distinguishing cannabis cultivars with similar cannabinoid content. Methods: In this study we analyzed terpenoid content of cannabis samples obtained from a single medical cannabis dispensary in California over the course of a year. Terpenoids were quantified by gas chromatography with flame ionization detection and peak identification was confirmed with gas chromatography mass spectrometry. Quantitative data from 16 major terpenoids were analyzed using hierarchical clustering analysis (HCA), principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA), and orthogonal partial least squares discriminant analysis (OPLS-DA). Results: A total of 233 samples representing 30 cultivars were used to develop a classification scheme based on quantitative data, HCA, PCA, and OPLS-DA. Initially cultivars were divided into five major groups, which were subdivided into 13 classes based on differences in terpenoid profile. Different classification models were compared with PLS-DA and found to perform best when many representative samples of a particular class were included. Conclusion: A hierarchy of terpenoid chemotypes was observed in the data set. Some cultivars fit into distinct chemotypes, whereas others seemed to represent a continuum of chemotypes. This study has demonstrated an approach to classifying cannabis cultivars based on terpenoid profile.
Article
Full-text available
This short communication examines the question whether the experimental data presented in a study by Merrick et al. are of clinical relevance. These authors found that cannabidiol (CBD), a major cannabinoid of the cannabis plant devoid of psychotropic effects and of great interest for therapeutic use in several medical conditions, may be converted in gastric fluid into the psychoactive cannabinoids delta-8-THC and delta-9-THC to a relevant degree. They concluded that “the acidic environment during normal gastrointestinal transit can expose orally CBD-treated patients to levels of THC and other psychoactive cannabinoids that may exceed the threshold for a positive physiological response.” They issued a warning concerning oral use of CBD and recommend the development of other delivery methods. However, the available clinical data do not support this conclusion and recommendation, since even high doses of oral CBD do not cause psychological, psychomotor, cognitive, or physical effects that are characteristic for THC or cannabis rich in THC. On the contrary, in the past decades and by several groups, high doses of oral CBD were consistently shown to cause opposite effects to those of THC in clinical studies. In addition, administration of CBD did not result in detectable THC blood concentrations. Thus, there is no reason to avoid oral use of CBD, which has been demonstrated to be a safe means of administration of CBD, even at very high doses.
Article
Full-text available
Many plant species produce mixtures of odorous and volatile compounds known as essential oils (EOs). These mixtures play important roles in Nature and have been utilized by mankind for different purposes, such as pharmaceuticals, agrochemicals, aromatherapy, and food flavorants. There are more than 3000 EOs reported in the literature, with approximately 300 in commercial use, including the EOs from Eucalyptus species. Most EOs from Eucalyptus species are rich in monoterpenes and many have found applications in pharmaceuticals, agrochemicals, food flavorants, and perfumes. Such applications are related to their diverse biological and organoleptic properties. In this study, we review the latest information concerning the chemical composition and biological activities of EOs from different species of Eucalyptus. Among the 900 species and subspecies of the Eucalyptus genus, we examined 68 species. The studies associated with these species were conducted in 27 countries. We have focused on the antimicrobial, acaricidal, insecticidal and herbicidal activities, hoping that such information will contribute to the development of research in this field. It is also intended that the information described in this study can be useful in the rationalization of the use of Eucalyptus EOs as components for pharmaceutical and agrochemical applications as well as food preservatives and flavorants.
Article
Full-text available
Aims: We have investigated the antihyperalgesic effects of limonene in mice that received intrathecal injection of gp120. Main methods: Male Swiss mice received gp120, IL-1β or TNF-α intrathecally or sterile saline as a control. A mechanicalsensitivity test was performed at 2 and 3h after the injection. Spinal cord and blood samples were isolated for protein quantification. Key findings: Intrathecal administration of gp120 increased mechanical sensitivity measured with an electronic Von Frey apparatus, at 2 and 3h after the injections. Limonene administered orally prior to gp120 administration significantly decreased this mechanical sensitivity at 3h after the gp120 injection. In addition, intrathecal injection of gp120 increased IL-1β and IL-10 in serum, and limonene prevented the ability of gp120 to increase these cytokines. Limonene also inhibited TNF-α and IL-1β-induced mechanical hyperalgesia. Western blot assay demonstrated limonene was capable of increasing SOD expression in the cytoplasm of cells from spinal cord at 4h after intrathecal IL-1β injection. Significance: These results demonstrate that gp120 causes mechanical hyperalgesia and a peripheral increase in IL-1β and IL-10, and that prior administration of limonene inhibits these changes. Also limonene modulates the activation of SOD expression in the spinal cord after spinal IL-1β application. The ability of limonene to inhibit the mechanical hyperalgesia induced by gp120, TNF-α and IL-1β emphasizes the anti-inflammatory action of limonene, specifically its ability to inhibit cytokine production and its consequences.
Article
Full-text available
Objective(s) Cerebral ischemia is often associated with cognitive impairment. Oxidative stress has a crucial role in the memory deficit following ischemia/reperfusion injury. α-Terpineol is a monoterpenoid with anti-inflammatory and antioxidant effects. This study was carried out to investigate the effect of α-terpineol against memory impairment following cerebral ischemia in rats. Materials and Methods Cerebral ischemia was induced by transient bilateral common carotid artery occlusion in male Wistar rats. The rats were allocated to sham, ischemia, and α-terpineol-treated groups. α-Terpineol was given at doses of 50, 100, and 200 mg/kg, IP once daily for 7 days post ischemia. Morris water maze (MWM) test was used to assess spatial memory and in vivo extracellular recording of long-term potentiation (LTP) in the hippocampal dentate gyrus was carried out to evaluate synaptic plasticity. Malondialdehyde (MDA) was measured to assess the extent of lipid peroxidation in the hippocampus. Results In MWM test, α-terpineol (100 mg/kg, IP) significantly decreased the escape latency during training trials (P<0.01). In addition, α-terpineol increased the number of crossings over the platform location and decreased average proximity to the target in probe trial (P<0.05). In electrophysiological recording, α-terpineol (100 mg/kg) facilitated the induction of LTP in the hippocampus which was persistent over 2 hr. α-Terpineol (100 and 200 mg/kg) also significantly lowered hippocampal MDA levels in rats subjected to cerebral ischemia. Conclusion These findings indicate that α-terpineol improves cerebral ischemia-related memory impairment in rats through the facilitation of LTP and suppression of lipid peroxidation in the hippocampus.
Article
Full-text available
Aim: The biopotential of the essential oils of the Greek aromatic plants Satureja thymbra and Satureja parnassica were investigated, together with their major components carvacrol, thymol, γ-terpinene and p-cymene. Materials and methods: Antioxidant and cancer cell cytotoxic properties were determined using 2,2-diphenyl-1-picrylhydrazyl and sulforhodamine B assays, respectively. The antiproliferative potential was studied against the MCF-7, A549, HepG2 and Hep3B cell lines. Results: S. thymbra oil possessed stronger antioxidant and antiproliferative capacity when tested on MCF-7 cells compared to S. parnassica oil. Thymol exhibited two-fold greater antioxidant potency than carvacrol, whereas γ-terpinene and p-cymene had no significant effect. Carvacrol was the most potent antiproliferative agent against A549 cells, while Hep3B cells were most sensitive to thymol. p-Cymene and γ-terpinene demonstrated negligible bioactivity. Conclusion: S. thymbra and S. parnassica essential oils exhibit significant but diverse antioxidant and antiproliferative activities, mainly attributed to their main components, carvacrol and thymol.
Article
Full-text available
Cannabis sativa L. is a prolific, but not exclusive, producer of a diverse group of isoprenylated resorcinyl polyketides collectively known as phytocannabinoids. The modular nature of the pathways that merge into the phytocannabinoid chemotype translates in differences in the nature of the resorcinyl side-chain and the degree of oligomerization of the isoprenyl residue, making the definition of phytocannabinoid elusive from a structural standpoint. A biogenetic definition is therefore proposed, splitting the phytocannabinoid chemotype into an alkyl-and a b-aralklyl version, and discussing the relationships between phytocannabinoids from different sources (higher plants, liverworts, fungi). The startling diversity of cannabis phytocannabinoids might be, at least in part, the result of non-enzymatic transformations induced by heat, light, and atmospheric oxygen on a limited set of major constituents (CBG, CBD, D 9-THC and CBC and their corresponding acidic versions), whose degradation is detailed to emphasize this possibility. The diversity of metabotropic (cannabinoid receptors), ionotropic (thermos-TRPs), and transcription factors (PPARs) targeted by phytocannabinoids is discussed. The integrated inventory of these compounds and their biological macromolecular end-points highlights the opportunities that phytocannabinoids offer to access desirable drug-like space beyond the one associated to the narcotic target CB 1 .
Article
Full-text available
Natural bicyclic sesquiterpenes, β-caryophyllene (BCP) and β-caryophyllene oxide (BCPO), are present in a large number of plants worldwide. Both BCP and BCPO (BCP(O)) possess significant anticancer activities, affecting growth and proliferation of numerous cancer cells. Nevertheless, their antineoplastic effects have hardly been investigated in vivo. In addition, both compounds potentiate the classical drug efficacy by augmenting their concentrations inside the cells. The mechanisms underlying the anticancer activities of these sesquiterpenes are poorly described. BCP is a phytocannabinoid with strong affinity to cannabinoid receptor type 2 (CB2), but not cannabinoid receptor type 1 (CB1). In opposite, BCP oxidation derivative, BCPO, does not exhibit CB1/2 binding, thus the mechanism of its action is not related to endocannabinoid system (ECS) machinery. It is known that BCPO alters several key pathways for cancer development, such as mitogen-activated protein kinase (MAPK), PI3K/AKT/mTOR/S6K1 and STAT3 pathways. In addition, treatment with this compound reduces the expression of procancer genes/proteins, while increases the levels of those with proapoptotic properties. The selective activation of CB2 may be considered a novel strategy in pain treatment, devoid of psychoactive side effects associated with CB1 stimulation. Thus, BCP as selective CB2 activator may be taken into account as potential natural analgesic drug. Moreover, due to the fact that chronic pain is often an element of cancer disease, the double activity of BCP, anticancer and analgesic, as well as its beneficial influence on the efficacy of classical chemotherapeutics, is particularly valuable in oncology. This review is focused on anticancer and analgesic activities of BCP and BCPO, the mechanisms of their actions, and potential therapeutic utility.
Article
Full-text available
Introduction: There is a large disparity between the ''cultural'' language used by patients using cannabis for self-medication and the ''chemical'' language applied by scientists to get a deeper understanding of cannabis effects in laboratory and clinical studies. The distinction between Sativa and Indica types of cannabis, and the different biological effects associated with them, is a major example of this. Despite the widespread use of cannabis by self-medicating patients, scientific studies are yet to identify the biochemical markers that can sufficiently explain differences between cannabis varieties. Methods: A metabolomics approach, combining detailed chemical composition data with cultural information available for a wide range of cannabis samples, can help to bridge the existing gap between scientists and patients. Such an approach could be helpful for decision-making, for example, when identifying which varieties of cannabis should be made legally available under national medicinal cannabis programs. In our study, we analyzed 460 cannabis accessions obtained from multiple sources in The Netherlands, including hemp-and drug-type cannabis. Results: Based on gas chromatography analysis of 44 major terpenes and cannabinoids present in these samples , followed by Multivariate Data Analysis of the resulting chromatographic data, we were able to identify the cannabis constituents that may act as markers for distinction between Indica and Sativa. This information was subsequently used to map the current chemical diversity of cannabis products available within the Dutch medicinal cannabis program, and to introduce a new variety missing from the existing product range. Conclusion: This study represents the analysis of the widest range of cannabis constituents published to date. Our results indicate the usefulness of a metabolomics approach for chemotaxonomic mapping of cannabis varieties for medical use.
Article
Full-text available
(-)-Guaiol, generally known as an antibacterial compound, has been found in many medicinal plants. Its roles in tumor suppression are still under investigation. In the study, we mainly focused on exploring its applications in dealing with non-small cell lung cancer (NSCLC) and the underlying mechanisms. Here, we show that (-)-Guaiol significantly inhibits cell growth of NSCLC cells both in vitro and in vivo. Further high throughput analysis reveals that RAD51, a pivotal factor in homologous recombination repair, is a potential target for it. The following mechanism studies show that (-)-Guaiol is involved in cell autophagy to regulate the expression of RAD51, leading to double-strand breaks triggered cell apoptosis. Moreover, targeting RAD51, which is highly overexpressed in the lung adenocarcinoma tissues, can significantly increase the chemosensitivity of NSCLC cells to (-)-Guaiol both in vitro and in vivo. All in all, our studies provide an attractive insight in applying (-)-Guaiol into NSCLC treatments and further suggest that knockdown of oncogenic RAD51 will greatly enhance the chemosensitivity of patients with NSCLC.
Chapter
Full-text available
In the 1960s several interesting compounds were isolated from the Cannabis plant. Today over 100 cannabinoids have been identified, across numerous varieties of Cannabis, which are structurally related to the main psychoactive ingredient ?9-tetrahydrocannabinol. This plant is a treasure trove of pharmacological compounds. Many of these compounds demonstrate unique properties and mechanisms apart from those of ?9-tetrahydrocannabinol; nonpsychotropic cannabidiol especially is being explored in pediatric clinical trials for the treatment of epilepsy. Cannabidiol and other cannabinoids may also represent nontoxic treatments with an exceedingly low potential for developing drug-addiction-related disorders. The aroma of Cannabis comprises over 120 terpenoid compounds, which are potent mediators of mammalian behavior when delivered at ambient air levels. ?-Caryophyllene is one of the most abundant terpenoids in the plant kingdom with cannabinoid receptor activity and has been shown to reduce cocaine self-administration in animals. The active ingredients on the Cannabis plant interact with or stimulate the endocannabinoid system, which underlies the mechanisms explaining potential benefits in drug abuse and addiction treatments.
Article
Full-text available
Δ(9)-tetrahydrocannabinolic acid A (THCA-A) is the acidic precursor of Δ(9)-tetrahydrocannabinol (THC), the main psychoactive compound found in Cannabis sativa. THCA-A is biosynthesized and accumulated in glandular trichomes present on flowers and leaves, where it serves protective functions and can represent up to 90% of the total THC contained in the plant. THCA-A slowly decarboxylates to form THC during storage and fermentation and can further degrade to cannabinol. Decarboxylation also occurs rapidly during baking of edibles, smoking, or vaporizing, the most common ways in which the general population consumes Cannabis. Contrary to THC, THCA-A does not elicit psychoactive effects in humans and, perhaps for this reason, its pharmacological value is often neglected. In fact, many studies use the term "THCA" to refer indistinctly to several acid derivatives of THC. Despite this perception, many in vitro studies seem to indicate that THCA-A interacts with a number of molecular targets and displays a robust pharmacological profile that includes potential anti-inflammatory, immunomodulatory, neuroprotective, and antineoplastic properties. Moreover, the few in vivo studies performed with THCA-A indicate that this compound exerts pharmacological actions in rodents, likely by engaging type-1 cannabinoid (CB1) receptors. Although these findings may seem counterintuitive due to the lack of cannabinoid-related psychoactivity, a careful perusal of the available literature yields a plausible explanation to this conundrum and points toward novel therapeutic perspectives for raw, unheated Cannabis preparations in humans.
Article
Full-text available
In order to complete a genetic model for the inheritance of chemotype in Cannabis, this paper explores the regulation of the propyl-/pentyl cannabinoid ratio. Plants almost pure in compounds with a C5 side chain are by far the most common, and such a chemotype can be considered a wild-type condition. Mutant progenitors with higher levels of the rarer cannabinoid THC-C3 (tetrahydrocannabivarin) were identified. Their propyl cannabinoid proportion in the total cannabinoid fraction (PC3) ranged from 14 to 69 %, which, through selective inbreeding, could be increased to highly specific lineage maxima. Inbred plants with maximised PC3 derived from the different progenitors, were then crossed with a pure C5 wild type and the PC3 distribution patterns of the F2s examined. Distinct patterns, compatible with oligogenic and polygenic segregation appeared. It was hypothesised that the PC3 regulating loci of the six source progenitors would be at least partially different, complementary, and additive in their phenotypical effect. So, high PC3 offspring from the different lineages were mutually crossed. Inbred lines derived from multi-cross hybrid combinations reached unprecedented PC3 levels of up to 96 % which supports the hypothesis. For the regulation of C3/C5 ratios, a model of a multiple locus A 1–A 2–…A n is proposed, with the pentyl- and propyl cannabinoid pathway being enhanced by alleles A pe1−n and A pr1−n, respectively.
Article
Full-text available
Objectives: Dependence and tolerance to opioid analgesics are major problems limiting their clinical application. α-Terpineol is a monoterpenoid alcohol with neuroprotective effects which is found in several medicinal plants such as Myrtus communis, Laurus nobilis, and Stachys byzantina. It has been shown that some of these medicinal plants such as S. byzantina attenuate dependence and tolerance to morphine. Since α-terpineol is one of the bioactive phytochemical constituent of these medicinal plants, the present study was conducted to investigate the effects of α-terpineol on morphine-induced dependence and tolerance in mice. Materials and methods: The mice were rendered dependent or tolerant to morphine by a 3-day administration schedule. The hot-plate test and naloxone-induced withdrawal syndrome were used to evaluate tolerance and dependence on morphine, respectively. To investigate a possible role for nitric oxide (NO) in the protective effect of α-terpineol, the NO synthase inhibitor, L-N(G)-nitroarginine methyl ester (L-NAME) and NO precursor, L-arginine, were used. Results: Administration of α-terpineol (5, 10, and 20 mg/kg, IP) significantly decreased the number of jumps in morphine dependent animals. Moreover, α-terpineol (20 and 40 mg/kg, IP) attenuated tolerance to the analgesic effect of morphine. The inhibitory effects of α-terpineol on morphine-induced dependence and tolerance were enhanced by pretreatment with L-NAME (10 mg/kg, IP). However, L-arginine (300 mg/kg, IP) antagonized the protective effects of α-terpineol on dependence and tolerance to morphine. Conclusion: These findings indicate that α-terpineol prevents the development of dependence and tolerance to morphine probably through the influence on NO production.
Article
Full-text available
In 2010 a review by Hazekamp and Grotenhermen covered controlled clinical trials of the years 2006-2009 on cannabis-based medicines, which followed the example of the review by Ben Amar (2006). The current review reports on the more recent clinical data available from 2010-2014. A systematic search was performed in the scientific database of PubMed, focused on clinical studies that were randomized, (double) blinded, and placebo-controlled. The key words used were: cannabis, marijuana, marihuana, hashish, cannabinoid(s), tetrahydrocannabinol, THC, CBD, dronabinol, Marinol, nabilone, Cannador, nabiximols and Sativex. For the final selection, only properly controlled clinical trials were retained. Open-label studies were excluded, except if they were a direct continuation of a study discussed here. Thirty-two controlled studies evaluating the therapeutic effects of cannabinoids were identified. For each clinical trial, the country where the project was held, the number of patients assessed, the type of study and comparisons done, the products and the dosages used, their efficacy and their adverse effects are described. Based on the clinical results, cannabinoids present an interesting therapeutic potential mainly as analgesics in chronic neuropathic pain and spasticity in multiple sclerosis. But a range of other indications also seem promising. CBD (cannabidiol) emerges as another valuable cannabinoid for therapeutic purposes besides THC.
Article
Full-text available
The control of hyperlipidemia plays a central role in cardiovascular disease. Previously, we have shown that camphene, a constituent of mastic gum oil, lowers cholesterol and triglycerides (TG) in the plasma of hyperlipidemic rats without affecting HMG-CoA reductase activity, suggesting that its hypocholesterolemic and hypotriglyceridemic effects are associated with a mechanism of action different than that of statins. In the present study, we examine the mechanism by which camphene exerts its hypolipidemic action. We evaluated the effect of camphene on the de novo synthesis of cholesterol and TG from [14C]-acetate in HepG2 cells, along with the statin mevinolin. Camphene inhibited the biosynthesis of cholesterol in a concentration-dependent manner, and a maximal inhibition of 39% was observed at 100 μM while mevinolin nearly abolished cholesterol biosynthesis. Moreover, treatment with camphene reduced TG by 34% and increased apolipoprotein AI expression. In contrast, mevinolin increased TG by 26% and had a modest effect on apolipoprotein AI expression. To evaluate the mode of action of camphene, we examined its effects on the expression of SREBP-1, which affects TG biosynthesis and SREBP-2, which mostly affects sterol synthesis. Interestingly, camphene increased the nuclear translocation of the mature form of SREBP-1 while mevinolin was found to increase the amount of the mature form of SREBP-2. The effect of camphene is most likely regulated through SREBP-1 by affecting MTP levels in response to a decrease in the intracellular cholesterol. We propose that camphene upregulates SREBP-1 expression and MTP inhibition is likely to be a probable mechanism whereby camphene exerts its hypolipidemic effect.
Article
Full-text available
Oxidative stress, as mediated by ROS, is a significant factor in initiating the development of age-associated cataracts; D-limonene is a common natural terpene with powerful antioxidative properties which occurs naturally in a wide variety of living organisms. It has been shown to have antioxidant effect; we found that D-limonene can effectively prevent the oxidative damage caused by H 2 O 2 and propose that the main mechanism underlying the inhibitory effects of D-limonene is the inhibition of HLECs apoptosis. In the present study, we used confocal-fluorescence microscopy, flow cytometry analysis, Hoechst staining, H 2 DCFDA staining, transmission electron microscopy, and immunoblot analysis; the results revealed that slightly higher concentrations of D-limonene (125–1800 μ M) reduced the H 2 O 2 -induced ROS generation and inhibited the H 2 O 2 -induced caspase-3 and caspase-9 activation and decreased the Bcl-2/Bax ratio. Furthermore, it inhibited H 2 O 2 -induced p38 MAPK phosphorylation. Thus, we conclude that D-limonene could effectively protect HLECs from H 2 O 2 -induced oxidative stress and that its antioxidative effect is significant, thereby increasing the cell survival rate.
Article
Full-text available
Background Glioblastoma is the most common and lethal type of primary brain tumor. β-Elemene, a natural plant drug extracted from Curcuma wenyujin, has shown strong anti-tumor effects in various tumors with low toxicity. However, the effects of β-elemene on malignant phenotypes of human glioblastoma cells remain to be elucidated. Here we evaluated the effects of β-elemene on cell proliferation, survival, stemness, differentiation and the epithelial-to-mesenchymal transition (EMT) in vitro and in vivo, and investigated the mechanisms underlying these effects. Methods Human primary and U87 glioblastoma cells were treated with β-elemene, cell viability was measured using a cell counting kit-8 assay, and treated cells were evaluated by flow cytometry. Western blot analysis was carried out to determine the expression levels of stemness markers, differentiation-related molecules and EMT-related effectors. Transwell assays were performed to further determine EMT of glioblastoma cells. To evaluate the effect of β-elemene on glioblastoma in vivo, we subcutaneously injected glioblastoma cells into the flank of nude mice and then intraperitoneally injected NaCl or β-elemene. The tumor xenograft volumes were measured every 3 days and the expression of stemness-, differentiation- and EMT-related effectors was determined by Western blot assays in xenografts. Results β-Elemene inhibited proliferation, promoted apoptosis, impaired invasiveness in glioblastoma cells and suppressed the growth of animal xenografts. The expression levels of the stemness markers CD133 and ATP-binding cassette subfamily G member 2 as well as the mesenchymal markers N-cadherin and β-catenin were significantly downregulated, whereas the expression levels of the differentiation-related effectors glial fibrillary acidic protein, Notch1, and sonic hedgehog as well as the epithelial marker E-cadherin were upregulated by β-elemene in vitro and in vivo. Interestingly, the expression of vimentin was increased by β-elemene in vitro; this result was opposite that for the in vivo procedure. Inhibiting β-catenin enhanced the anti-proliferative, EMT-inhibitory and specific marker expression-regulatory effects of β-elemene. Conclusions β-Elemene reversed malignant phenotypes of human glioblastoma cells through β-catenin-involved regulation of stemness-, differentiation- and EMT-related molecules. β-Elemene represents a potentially valuable agent for glioblastoma therapy.
Article
(-)-Linalool is the major floral scent occurring mainly in families Lamiaceae, Lauraceae and Rutaceae and is the main active compound of lavender oil. The purpose of this study was to reveal the influence of subchronic systemic treatment with (-)-linalool on the metabolic activity of CYP2A, 2B, 2C6, 2C11 and 3A in rat liver microsomes (RLM). The second aim was to reveal possible inhibitory effect of (-)-linalool on CYP2C6 in vitro. Wistar albino male rats were treated with (-)-linalool intragastrically in doses of 40, 120, and 360 mg/kg/day for 13 days. Treatment with (-)-linalool at the dose of 360 mg/kg increased the metabolic activity of CYP2A assessed with testosterone as a probe substrate. (-)-Linalool showed weak competitive inhibition of CYP2C6 in rat liver microsomes, with IC50 of 84 μM with use of diclofenac as a probe substrate.
Article
Canniprene (1), an isoprenylated bibenzyl unique to Cannabis sativa, can be vaporized and therefore potentially inhaled from marijuana. Canniprene (1) potently inhibited the production of inflammatory eicosanoids via the 5-lipoxygenase pathway (IC50 0.4 μM) and also affected the generation of prostaglandins via the cyclooxygenase/microsomal prostaglandin E2 synthase pathway (IC50 10 μM), while the related spiranoid bibenzyls cannabispiranol (2) and cannabispirenone (3) were almost inactive in these bioassays. The concentration of canniprene (1) was investigated in the leaves of 160 strains of C. sativa, showing wide variations, from traces to >0.2%, but no correlation was found between its accumulation and a specific phytocannabinoid profile.
Article
Background and aims: Beta-caryophyllene (BCP) is a plant-derived FDA approved food additive with anti-inflammatory properties. Some of its beneficial effects in vivo reported to involve activation of cannabinoid 2 receptors (CB2) that are predominantly expressed in immune cells. Herein, we evaluated the translational potential of BCP using a well-established model of chronic and binge alcohol-induced liver injury. Methods: In this study we investigated the effects of BCP on liver injury induced by chronic plus binge alcohol feeding in mice in vivo by using biochemical assays, real-time PCR and histology analyses. Serum and hepatic BCP levels were also determined by GC/MS. Results: Chronic treatment with BCP attenuated the chronic and binge alcohol-induced liver injury and inflammation by attenuating the pro-inflammatory phenotypic `M1` switch of Kupffer cells and by decreasing the expression of vascular adhesion molecules ICAM-1, E-Selectin and P-Selectin, as well as the neutrophil infiltration. It also beneficially influenced hepatic metabolic dysregulation (steatosis, protein hyperacetylation, and PPAR-ɑ signaling). The above mentioned protective effects of BCP against alcohol-induced liver injury were attenuated in CB2 knockout mice, indicating that the beneficial effects of this natural product in liver injury involve CB2 receptor activation. Following acute or chronic administration BCP was detectable both in the serum and liver tissue homogenates but not in the brain. Conclusions: Given the safety of BCP in humans this food additive has a high translational potential in treating or preventing hepatic injury associated with oxidative stress, inflammation and steatosis.
Article
The regulatory effect of β-eudesmol, which is an active constituent of Pyeongwee-San (KMP6), is evaluated for allergic reactions induced by mast cell degranulation. Phorbol 12-myristate 13-acetate (PMA) plus calcium ionophore A23187-stimulated human mast cell line, HMC-1 cells, and compound 48/80-stimulated rat peritoneal mast cells (RPMCs) are used as the in vitro models; mice models of systemic anaphylaxis, ear swelling, and IgE-dependent passive cutaneous anaphylaxis (PCA) are used as the in vivo allergic models. The results demonstrate that β-eudesmol suppressed the histamine and tryptase releases from the PMA plus calcium ionophore A23187-stimulated HMC-1 cells. β-eudesmol inhibits the expression and activity of histidine decarboxylase in the activated HMC-1 cells. In addition, β-eudesmol inhibits the levels of histamine and tryptase released from the compound 48/80-stimulated RPMCs. Furthermore, β-eudesmol decreases the intracellular calcium level in the activated RPMCs. β-eudesmol also decreases the compound 48/80-induced mortality and ear swelling response. β-eudesmol suppresses the serum levels of histamine, IgE, IL-1β, IL-4, IL-5, IL-6, IL-13, and VEGF under PCA mice as well as PCA reactions. Therefore, the results from this study indicate the potential of β-eudesmol as an anti-allergic drug with respect to its pharmacological properties against mast cell-mediated allergic reactions. This article is protected by copyright. All rights reserved.