Believe it or not, CBD oils vary greatly in concentration, quality, and more. The amount of CBD they contain per bottle or capsule can usually be found on the packaging percentages instead, such as 4%, 10%, or 20% cannabidiol (CBD). CBD oil is derived from hemp or cannabis plants—both of which. Cannabis oils may contain various concentrations of CBD, in these products, depending on the preparation method used . . in which CBD levels are higher than the CBD levels in the plant source are novel in food” . Some patients believe CBD has the most medicinal benefit of all the cannabis compounds. first shop in Italy dedicated to cannabis, sprays water on hemp plants in Milan. the difference in the amount of CBD these products contain is huge. It is the higher concentration that makes CBD beneficial in the.
of 4) Concentration CBD In The Plant Level
Anatomical details of Cannabis stem. A Stem of an adult plant ca 2 months ; B The stem can be peeled off and shows a lignified core and a cortex with bast fibers. C Longitudinal section of hemp stem stained with toluidine blue showing the cortex with a bundle of bast-fibers white asterisk and the core with xylem vessels black asterisk.
This heterogeneous cell wall composition makes hemp stem an interesting model to study secondary cell wall biosynthesis, in particular the molecular events underlying the deposition of cortical gelatinous bast fibers and core woody fibers. Cannabis woody fibers a. Hemp bast fibers are used in the biocomposite sector as a substitute of glass fibers. The automotive industry is particularly keen on using hemp bast fibers to produce bioplastics: Beyond the applications in the construction and automotive industries, hemp fibers are attractive also in the light of their natural antibacterial property.
Hemp bast fibers have been indeed described as antibacterial Hao et al. This property is linked to the chemical composition of hemp bast fibers: These compounds possess known antibacterial properties Kiprono et al. More recently hemp hurd powder showed antibacterial properties against Escherichia coli Khan et al. Since the hurd has a higher lignin content than the bast fibers, its antibacterial property may be linked to lignin-related compounds such phenolic compounds, as well as alkaloids and cannabinoids Appendino et al.
Numerous chemicals are produced in hemp through the secondary metabolism. They include cannabinoids, terpenes and phenolic compounds Flores-Sanchez and Verpoorte, and will be further described in the next sections. Although the pharmacological properties of cannabinoids have extensively been studied and are the most recognized hemp bioactives, the other components have no reasons to envy them, as they have also been associated with potent health-promoting properties.
Research on Cannabis phytochemicals, as well as the widespread therapeutic use of Cannabis products, has been limited due to various reasons, including illegality of cultivation due to its psychoactivity and potential for inducing dependence , variability of active components, and low abundance of some of them in planta. Further attentions is now drawn toward non-THC Cannabis active components, which may act synergistically and contribute to the pharmacological power and entourage effects of medicinal-based Cannabis extract Russo, Phytocannabinoids represent a group of C21 or C22 for the carboxylated forms terpenophenolic compounds predominantly produced in Cannabis.
They have also been reported in plants from the Radula and Helichrysum genus Appendino et al. More than 90 different cannabinoids have been reported in the literature, although some of these are breakdown products ElSohly and Slade, ; Brenneisen, ; Radwan et al.
In this review, we will focus on the most abundant compounds found in the drug- and fiber-type Cannabis. CBCA has been reported to dominate in the cannabinoid fraction of young plants and to decline with maturation Meijer et al. The phytocannabinoid acids are non-enzymatically decarboxylated into their corresponding neutral forms, which occur both within the plant and, to a much larger extent, upon heating after harvesting Flores-Sanchez and Verpoorte, Phytocannabinoids accumulate in the secretory cavity of the glandular trichomes, which largely occur in female flowers and in most aerial parts of the plants, as further described in the next section.
They have also been detected in low quantity in other parts of the plants including the seeds Ross et al. The level of phytocannabinoids in hempseeds, and thereby of hempseed oil, should be very low as the kernel contains only trace amount of THC or CBD Leizer et al.
However, higher THC concentrations are found on the outside surface of the seed coat, possibly as the result of contamination with plant leaves or flowers Ross et al.
Cannabinoids in the leaves have been shown to decrease with the age and along the stem axis, with the highest levels observed in the leaves of the uppermost nodes Pacifico et al.
Cannabinoid contents in the stem are scarce in the literature. An analysis performed on the dust obtained from the top section of the stem of fiber-type hemp low percentage of bast fibers revealed a low THC and CBD content 0.
Summary of the concentrations in cannabinoids found in different parts of the hemp plants, in vitro hairy roots, and some commercial medicinal products. The biosynthesis of cannabinoids from C. The precursors of cannabinoids actually originate from two distinct biosynthetic pathways: Three oxidocyclases will then be responsible for the diversity of cannabinoids: Propyl cannabinoids cannabinoids with a C3 side-chain, instead of a C5 side-chain , such as tetrahydrocannabivarinic acid THCVA , synthetized from a divarinolic acid precursor, have also been reported in Cannabis Flores-Sanchez and Verpoorte, Schematic view of the biosynthetic pathways leading to the Cannabis secondary metabolites discussed in this review.
Transport of precursors is represented by dashed arrows, while direct catalytic reactions are depicted by bold arrows. See text for detailed pathways. The pharmacology of phytocannabinoids has previously been reviewed elsewhere Pacher et al.
Most of the biological properties related to cannabinoids rely on their interactions with the endocannabinoid system in humans. The endocannabinoid system includes two G protein-coupled cannabinoid receptors, CB1 and CB2, as well as two endogenous ligands, anandamide and 2-arachidonylglycerol. Endocannabinoids are thought to modulate or play a regulatory role in a variety of physiological processing including appetite, pain-sensation, mood, memory, inflammation, insulin, sensitivity and fat and energy metabolism De Petrocellis et al.
In addition to being present in the central nervous system and throughout the brain, CB1 receptors are also found in the immune cells and the gastrointestinal, reproductive, adrenal, heart, lung and bladder tissues, where cannabinoids can therefore also exert their activities.
CB2 receptors are thought to have immunomodulatory effects and to regulate cytokine activity. But THC has actually more molecular targets than just CB1 and CB2 receptors, and exhibit potent anti-inflammatory, anti-cancer, analgesic, muscle relaxant, neuro-antioxidative De Petrocellis et al. However, THC has been also associated with a number of side effects, including anxiety, cholinergic deficits, and immunosuppression Russo, CBDA is the most prevalent phytocannabinoid in the fiber-type hemp, and the second most important in the drug chemotypes.
CBD itself has been shown in in vitro and animal studies to possess, among others, anti-anxiety, anti-nausea, anti-arthritic, anti-psychotic, anti-inflammatory, and immunomodulatory properties Burstein, CBD is a very promising cannabinoid as it has also shown potential as therapeutic agents in preclinical models of central nervous system diseases such as epilepsy, neurodegenerative diseases, schizophrenia, multiple sclerosis, affective disorders and the central modulation of feeding behavior Hill et al.
Interestingly, CBD presents also strong anti-fungal and anti-bacterial properties, and more interestingly powerful activity against methicillin-resistant Staphylococcus aureus MRSA Appendino et al. CBC presents notably anti-inflammatory Delong et al. It thus affects cells of the immune system more than the central nervous system, as reviewed in McPartland and Russo, Current cannabinoid-based therapeutic treatments is limited to special cases, i.
As mentioned earlier, the recreational and medical use of Cannabis as well as of THC and other synthetic cannabinoids have also been associated with numerous side effects.
Two recent reviews Volkow et al. When adjusted for confounders such as cigarette smoking, the impact of short- and long-term use appear to be similar for both types of consumption and are directly linked to the level of THC or its synthetic analog.
Effects of short-term use include memory and cognitive deficits, impaired motor coordination, and psychosis. Long-term use of THC has been associated to an increased risk of addiction, cognitive impairment, altered brain development when initial use was done early in adolescence, and an increased risk of chronic psychosis disorder including schizophrenia.
The protective role that CBD could play to alleviate these negative effects is now well established and documented Iseger and Bossong, Terpenes form the largest group of phytochemicals, with more than molecules identified in Cannabis Rothschild et al.
Terpenes are responsible for the odor and flavor of the different Cannabis strains. They have therefore likely contributed to the selection of Cannabis narcotic strains under human domestication Small, Terpenes are classified in diverse families according to the number of repeating units of 5-carbon building blocks isoprene units , such as monoterpenes with 10 carbons, sesquiterpenes with 15 carbons, and triterpenes derived from a carbon skeleton.
Terpene yield and distribution in the plant vary according to numerous parameters, such as processes for obtaining essential oil, environmental conditions, or maturity of the plant Meier and Mediavilla, ; Brenneisen, Mono- and sesquiterpenes have been detected in flowers, roots, and leaves of Cannabis , with the secretory glandular hairs as main production site. Monoterpenes dominate generally the volatile terpene profile from 3.
Triterpenes have also been detected in hemp roots, as friedelin and epifriedelanol Slatkin et al. Terpenes, along with cannabinoids, have successfully been used as chemotaxonomic markers in Cannabis , as they are both considered as the main physiologically active secondary metabolites Fischedick et al.
When grown in standardized conditions, a significant and positive correlation was found between the level of terpenes and cannabinoids Fischedick et al. This may be explained by the fact that mono- and sesquiterpenes are synthesized in the same glandular trichomes in which the cannabinoids are produced Meier and Mediavilla, This association was, however, not confirmed on a larger panel of samples coming from different origins Elzinga et al.
Whereas the cytosolic mevalonic acid MVA pathway is involved in the biosynthesis of sesqui-, and tri-terpenes, the plastid-localized MEP pathway contributes to the synthesis of mono-, di-, and tetraterpenes Bouvier et al. MVA and MEP are produced through various and distinct steps, from two molecules of acetyl-coenzyme A and from pyruvate and D -glyceraldehydephosphate, respectively. FPP serves as a precursor for sesquiterpenes C15 , which are formed by terpene synthases and can be decorated by other various enzymes.
Two FPP molecules are condensed by squalene synthase SQS at the endoplasmic reticulum to produce squalene C30 , the precursor for triterpenes and sterols, which are generated by oxidosqualene cyclases OSC and are modified by various tailoring enzymes. GPP is the immediate precursor for monoterpenes Kempinski et al. Terpenes are lipophilic compounds that easily cross membranes and the blood-brain barrier in particular Fukumoto et al.
They present a wide-array of pharmacological properties, which have recently been described in several reviews Russo, ; Singh and Sharma, The biological activities of D-limonene, also commonly found in Citrus essential oils, have been well described in the literature. It notably exhibits potent anti-cancer, anxiolytic and immunostimulating properties in humans Komori et al.
Linalool, commonly found in Lavandula angustifolia , possesses similar properties to the ones described for its monoterpene counterparts, i. Interestingly, it selectively binds to the CB2 receptor and could therefore technically be considered as a phytocannabinoid Gertsch et al. These triterpenes are key contributors to the pharmacological properties of numerous medicinal herbs Kirby et al.
Phenolic compounds, also known as phenylpropanoids, constitute one of the most widely distributed group of secondary metabolites in the plant kingdom. They present more than 10, different structures, including phenolic acids, such benzoic and hydroxycinnamic acids, flavonoids such as flavonols and flavones, stilbenes and lignans Andre et al. In Cannabis , about 20 flavonoids have been identified, mainly belonging to the flavone and flavonol subclasses Flores-Sanchez and Verpoorte, Phenolic amides and lignanamides have also been described in Cannabis fruits and roots Sakakibara et al.
The lignanamides belong to the lignan class of compounds and include cannabisin-like compounds of the types A-, B-, C-, D-, E-, F-, and G and grossamide Flores-Sanchez and Verpoorte, Similar compounds such as cannabisin D, have been described in Cannabis leaves, where it was strongly induced upon the UV-C treatment Marti et al. Interesting amounts of lignans were recently found in the hydrophilic extract of hemp seeds. The hemp seed lignan profile was shown to be dominated by syringaresinol and medioresinol, followed by secoisolariciresinol, lariciresinol, and pinoresinol Smeds et al.
Hemp seeds contain, however, about times less total lignans 32 mg of total lignans per g of dry weight than flax seeds, a well-known source of lignans. Nineteen stilbenes have been isolated in Cannabis with characteristic structural backbones such as spirans, phenanthrenes and bibenzyls Flores-Sanchez and Verpoorte, Interestingly, bibenzyl stilbenes, including the putative 3- O -methylbatatasin, were strongly induced in Cannabis leaves by UV radiations Marti et al.
Routes to the major classes of phenolic compounds involve i the core phenylpropanoid pathway from phenylalanine to an activated hydroxy cinnamic acid derivative p-coumaroyl CoA , via the actions of the phenylalanine-ammonia-lyase PAL , cinnamate 4-hydroxylase C4H, a cytochrome P and 4-coumarate-CoA ligase 4CL , as well as specific branch pathways for the formation of ii simple esters, lignins and lignans, iii flavonoids, iv coumarins, and v stilbenes Andre et al.
Although the flavonoid pathway has been extensively studied in several plants, there is no specific data on the biosynthesis of flavonoids in Cannabis. Each pinoresinol can then be further enantiospecifically reduced to lariciresinol and secoisolariciresinol Dalisay et al. The key molecular events associated with the biosynthesis of lignanamides are still unknown.
The structure of these molecules suggests, however, a condensation of the precursors tyramine and CoA-esters of coumaric, caffeic, and coniferic acid Flores-Sanchez and Verpoorte, , followed by an oxidative coupling reaction catalyzed by a dirigent protein, as described for lignans. Naringenin chalcone is rapidly isomerized by the enzyme chalcone isomerase CHI to form naringenin, the branch point of flavonols on one hand and flavones on the other one.
Dihydrokaempferol and dihydroquercetin are substrates of flavonol synthase FLS , which catalyzes the production of the flavonols kaempferol and quercetin, respectively. Naringenin may alternatively be converted to apigenin, by a reaction catalised by a flavone synthase FNS.
In plants, phenolic compounds may act as antioxidants under certain physiological conditions and, thereby, protect plants against oxidative stress. In humans, it was shown that there is a correlation between dietary phenolic compound intake and a reduced incidence of chronic diseases such as cancers, cardiovascular and neurodegenerative diseases Arts and Hollman, , but these positive health effects may not be entirely explained by the phenolic antioxidant properties, as they are poorly bioavailable.
Phenolic compounds may induce the up-regulation of endogenous antioxidant enzymes in vivo , due to their ability to act as pro-oxidants and generate Reactive Oxygen Species ROS Halliwell et al.
They may also exert their action through non-specific protein binding interactions Gertsch et al. The flavones and flavonols found in Cannabis exert a wide range of biological effects, including properties shared by terpenes and cannabinoids. They present anti-inflammatory, anti-cancer and neuro-protective properties as reviewed in Andre et al.
In addition, apigenin has been shown to possess anxiolytic Murti et al. The specific cannflavin A et B are potent anti-inflammatory compounds, via inhibition of prostaglandin E2 and 5-lipoxygenase Werz et al. Health-related studies concerning lignanamides are scarce and showed in vitro anti-inflammatory Sun et al. Lignans in general show a wide array of health-promoting properties including antioxidant, antiviral, antidiabetic, antitumorigenic and anti-obesity activities.
Interestingly, secoisolariciresinol, lariciresinol and pinoresinol are converted into enterolignans by the anaerobic intestinal microflora, which are mammalian oestrogen precursors phyto-oestrogens Wang et al.
Due to the structural similarity of enterolignans with mammalian oestrogens, these compounds are potentially interesting for combating some hormone-dependent cancers.
The mechanisms of action of the lignans are, however, complex, with multiple targets involved Sainvitu et al. It is now well accepted that the health benefits of fruits, vegetables and other plant foods are due to the synergy or interactions between the different bioactive compounds or other nutrients present in the whole foods, and not to the action of a sole compound Liu, Similarly, Cannabis -based therapeutics exert their pharmacological effects in humans via synergistic or antagonistic interactions between the various phytochemicals described above.
These interactions may occur through various mechanisms including: A good example is the stronger muscle-antispastic effect of a Cannabis extract compared to pure THC, which represents an important finding for the treatment of multiple sclerosis Wagner and Ulrich-Merzenich, Non-THC cannabinoids have shown positive influence on the side effects induced by THC such as anti-anxiety activities.
CBD may also reduce the induced cognitive and memory deficits in subjects smoking Cannabis Wright et al. Terpenes may also alter the pharmacokinetics of THC by increasing the blood-brain barrier permeability. This characteristic has notably been used to patent a transdermal patch, which delivers cannabinoids into the bloodstream by using a terpene as a permeation agent Smith, Terpenes may also modulate the affinity of THC for the CB1 receptor and interact with neurotransmitter receptors, which may support contributions of terpenes on cannabinoid-mediated analgesic and psychotic effects McPartland and Russo, ; Russo, In view of the potential of phytocannabinoid-terpene synergy, it has been suggested to tailor novel therapeutic treatments such as CBD-terpene extracts to be used against acne, MRSA, depression, anxiety, insomnia, dementia and addiction Russo, Finally, there is an example of predator-targeted synergy between terpenes and phytocannabinoids in the Cannabis plant itself: Trichomes are epidermal protuberances covering the leaves, bracts and stems of plants and some of them, like the glandular trichomes, are capable of secreting or storing secondary metabolites as a defense mechanism.
Several papers have focused on the characterization of these specialized structures using -omics Wang et al. An -omics database TrichOME; available at: Additionally, several procedures in some instances supported by a video demonstration; e. Hemp has different types of trichomes Figures 3A—F which belong to two categories, i.
Capitate sessile, capitate stalked and bulbous hemp trichomes are secretory structures Figures 3C—F. A Unicellular non-glandular trichome; B cystolythic trichomes; C capitate sessile trichome; D capitate-stalked trichome; E simple bulbous trichome; F complex bulbous trichome.
Images kindly provided by Dr. In Cannabis THCA is accumulated in the heads glands of both capitate-stalked and capitate sessile trichomes, but in the former the content is higher Mahlberg and Kim, The accumulation in the storage cavity is due to the cytotoxicity of cannabinoids: Heterologous expression of THCAS fused to GFP in tobacco leads to fluorescence of the trichome heads, thereby confirming the localization of the enzyme in the storage cavity Sirikantaramas et al. Depending on their color, hemp glandular trichomes show different secretory phases Mahlberg and Kim, According to the current model cannabinoids are produced via terpenes secreted by plastids present in the disk cells and phenols stored in their vacuole Mahlberg and Kim, Subsequently vesicles are released into the cavity together with fibrillar matrix originating from the cell walls of the disk cells.
The fibrillar matrix is transported to the subcuticular cell wall and contributes to its thickening via yet unidentified mechanisms Mahlberg and Kim, Besides cannabinoids, Cannabis trichomes produce other secondary metabolites, namely terpenes see previous paragraph on Cannabis phytochemicals , which are responsible for the typical plant aroma Russo, Among the Cannabis terpenes of low abundance, is nerolidol 0.
Given the pharmacological importance of these compounds, it would be interesting to devise engineering strategies aiming at either boosting the secondary metabolism, or increasing the density of trichomes in Cannabis. Among the possible genetic engineering approaches, it is here worth mentioning two examples recently reported in Artemisia annua. We will here discuss only these two examples, as further discussion on how to scale up the production of cannabinoids is presented later in this review.
It has been recently shown that the transformation of A. The rol genes are known for their stimulatory action on plant secondary metabolism Bulgakov, The study on A. An additional study on A. The hydrolytic enzyme favors the release of active plant growth regulators from the conjugates stored in the plastids, thereby favoring trichome formation, as well as biomass production and leaf area Singh et al.
It would be interesting to devise an engineering strategy aimed at increasing the density of trichomes in Cannabis , by adopting a similar strategy. In this section of the review we will: The cultivation of Cannabis is severely regulated in many countries; therefore alternative in vitro growth techniques are receiving a lot of attention. Methods to multiply C. It was shown that micro-propagated plants are genetically stable; therefore the method is appropriate and useful for the clonal multiplication of this important crop Lata et al.
A protocol has also been developed for the propagation of hemp via the synthetic seed technology. According to this procedure, axillary buds or nodal segments are encapsulated in calcium alginate beads Lata et al.
This system was shown to allow the successful growth of homogeneous and genetically stable Cannabis plants even after 6 months of storage Lata et al. To set up a successful Cannabis transformation protocol, the mastery of in vitro culture techniques is necessary: Organ regeneration, in particular shoots, can be quite cumbersome and therefore the screening of different plant growth regulator concentrations and combinations has to be carried out to find the right culture medium composition.
Cannabis sativa is a notorious recalcitrant plant to transformation, because the regeneration efficiencies are quite low and dependent upon the cultivar, tissue, plant age and growth regulator combination Slusarkiewicz-Jarzina et al. As an example, although successful transformation of hemp calli via Agrobacterium tumefaciens was reported by Feeney and Punja , the undifferentiated cells failed to regenerate the shoots.
The cells were transformed with phosphomannose isomerase and colorimetric assays showed successful expression of the transgene. Nevertheless some success in hemp regeneration was reported and shown to be linked to the choice of specific plant growth regulators.
For example the addition of thidiazuron TDZ , which has cytokinin-like activity, was shown to increase the development of shoots in hemp explants Lata et al. Cannabis transformation protocols using plant explants thereby avoiding the passage to undifferentiated cells have been described for several important crops e. Notably, successful transformation of hemp plants was reported by MacKinnon et al. Additionally a patent application was filed describing Cannabis transformation using 1—2 cm hypocotyl explants, the plant growth regulators zeatin and 6-benzylaminopurine BAP for shoot regeneration Sirkowski, An additional system offering interesting applications for the industrial production of compounds showing pharmaceutical effects in humans is the hairy root system, a type of Agrobacterium -transformed plant tissue culture used to study plant metabolic processes.
Transformation of hemp and subsequent establishment of hairy root culture has been described by Wahby et al. In this study hypocotyls were found to be the most responsive tissue for infection. The hairy root system is very interesting for the production of secondary metabolites in medicinal plants Jiao et al.
The hairy root system is characterized by hormone-independent high growth rate and by the same metabolic potential as the original organ Pistelli et al. A protocol for the establishment of hairy roots from Cannabis callus cultures has also been described Farag and Kayser, The authors found that after 28 days of cultivation in the dark, a peak could be observed in the accumulation of cannabinoids in culture media supplemented with different concentrations of indoleacetic acid IAA.
The production of cannabinoids in hemp hairy root cultures can be then further implemented with adsorbents to avoid toxicity issues a more detailed discussion concerning possible ways to avoid toxicity is present in the section dedicated to heterologous plant hosts.
In alternative, inducible promoters can be used, like for instance the glucocorticoid-inducible promoter, which was already shown to be effective in inducing a controlled, reversible and dosage-dependent expression of GFP in Catharanthus roseus hairy roots Hughes et al. Plant cell suspension cultures offer important advantages, as they can be transformed and then cultivated in bioreactors for the production of useful metabolites Weathers et al.
Cannabis callus cultures are not able to produce any cannabinoids, irrespective of the chemotypes drug-, hybrid-, or fiber-type used as mother plants or growth regulators used in the culture medium Pacifico et al. The transformation of hemp cell suspension cultures with genes involved in specific metabolic pathways can offer the possibility of enhancing the production of important classes of metabolites such as cannabinoids but also of others with potential pharmacological use.
In this paragraph we will discuss about potential biotechnological approaches to boost the production of cannabinoids in Cannabis cell suspension culture. It is important to mention here that two transcription factors belonging to the MYB family were already shown to be preferentially expressed in Cannabis glands Marks et al.
These genes show homology with Arabidopsis thaliana MYB and MYB12, which are known to be involved in the tolerance to oxidative stress and flavonol biosynthesis, respectively Marks et al.
The expression of these transcription factors in an inducible manner is a strategy worth being tested for the production of cannabinoids. The inducible expression will limit the negative effects caused by the toxicity of the accumulating cannabinoids during the growth of the transformed plant cells as more thoroughly described in the next section.
Workflow showing the achievements in green and potential future approaches in light blue to produce cannabinoids in cultures of Cannabis , as well as other plant hosts. In addition to the genetic engineering approach, plant cell suspension cultures can be elicited to boost the production of secondary metabolites.
The literature is rich in examples concerning the increased expression of secondary metabolites in plant cells elicited with different factors reviewed recently by Ncube and Van Staden, Both biotic and abiotic stress factors can indeed be used to re-direct the plant metabolism: In hemp suspension cells, elicitation with biotic and abiotic elicitors did not induce an increase in cannabinoids Flores-Sanchez et al.
It is here worth mentioning the effect of a so far neglected element, silicon Si. Despite being a non-essential element for plant growth, Si is known to increase plant vigor and to alleviate the effects of exogenous stresses Epstein, Very recently Si was shown to alleviate the effects of salt stress and to induce the production of chlorogenic acid in Lonicera japonica Gengmao et al. Given the stimulatory effects that Si has on plant metabolism, it is interesting to further investigate, from a molecular perspective, the effects of Si supplementation on Cannabis secondary metabolite production.
Cyclodextrins have also been used in plant cell suspension cultures to enhance the production of various non-polar metabolites such as stilbenes Yang et al. They are known to form inclusion complexes with lipophilic compounds, including cannabinoids Hazekamp and Verpoorte, , in their hydrophobic cavity, thereby improving metabolite solubility in an aqueous environment.
It would therefore be worth investigating the effect of cyclodextrins on the production of the non-polar cannabinoids in hemp suspension cell cultures. For example synthetic biology could be used to recreate the cannabinoid biosynthetic pathway in heterologous plant cells via the expression of THCAS, together with the upstream enzymes involved in the synthesis of CBG, i.
Examples for the occurrence of metabolons exist in plants for pathways involving, e. Entire metabolic pathways can be engineered via the use of synthetic metabolons enabling the association of enzymes in close proximity: One possible way to assemble a synthetic metabolon is via the use of a scaffolding protein enabling the association of the enzymes Singleton et al. The assembly of multimodular constructs for expression in plants is no longer an insurmountable challenge, thanks to the development of methods like the Gateway-mediated cloning reviewed by Dafny-Yelin and Tzfira, , Golden Gate Binder et al.
When cannabinoids are produced in heterologous plant hosts, toxicity effects have to be taken into account, as it was shown that THCA and CBGA cause cell death via apoptosis in cells of Cannabis and tobacco BY-2 Sirikantaramas et al. For plant cell suspension cultures cultivated in bioreactors, the in situ product removal via a two-phase culture system might be useful to favor the accumulation of the toxic metabolites produced in sites which are separated from the cells Cai et al.
The use of adsorbents in the culture medium can not only sequester the toxic compounds, but also stimulate the secondary metabolite biosynthesis Cai et al. This approach has been recently proposed in A. The authors induced the formation of an artificial compartment generated by membranes deriving from endocytosis and the endoplasmic reticulum-vacuole trafficking via the expression of a truncated SNARE protein, AtSYP SCs are potentially addictogenic because these substances can increase dopamine secretion within the nucleus accumbens and the ventral tegmental area.
Intense and severe cravings have also been reported. An increasing number of nonfatal intoxications, as well as deaths, after presentation to the emergency room or in consultation have been reported, especially in young people. THC is the psychoactive principle of cannabis, inducing the cannabis inebriation sought by many users.
Its addictive potential and negative consequences are now well known. CBD seems not to induce euphoria and seems to have antipsychotic, anxiolytic, antiepileptic, and anti-inflammatory properties. According to an evaluation in by the Institute of Medicine in the United States on cannabis as a medication, the future of medical cannabis resides in isolating its cannabinoid components and their synthetic derivatives.
Various forms of cannabis have been studied to ascertain the therapeutic properties of cannabis. It has been approved in several countries Canada, Europe , but not in the United States, as an adjunctive therapy in the treatment of spastic pain in patients with neurological disorders. A meta-analysis reviewed randomized clinical trials worldwide of medical cannabis and cannabinoids from through The most frequently studied cannabinoid forms were medications produced by pharmaceutical companies: This study included only two trials using plant-based cannabis smoked and vaped.
The same level of proof was shown for nabiximols or smoked THC in the treatment of chronic cancer pain and neuropathic pain.
This meta-analysis showed that CBD was not significantly more efficient in treating psychosis than a usual antipsychotic, such as amisulpiride, or depression compared with nabiximols. Finally, one very small crossover trial with six patients was not able to detect an effect of cannabinoids on intraocular pressure.
A systematic review by the American Academy of Neurology examined publications from through November concerning the use of cannabinoids in the treatment of multiple sclerosis, movement disorders, and epilepsy. The other formulations seemed to be effective in these indications, but with lower levels of proof. Proof was insufficient to conclude as to the efficacy of smoked cannabis. In other neurological indications, such as Huntington disease and Tourette syndrome, proofs were judged insufficient.
Cannabinoids would seem to have some therapeutic interest in the following indications: However, there are currently insufficient levels of proof. Indeed, a Cochrane review from , for example, concluded that there were insufficient levels of proof for cannabinoids in the treatment of epilepsy. They remain the subject of preclinical and human research.
In animal studies, CBD has shown significant antiepileptic activity, reducing seizure severity. Recent studies in young patients suffering from severe, treatment-resistant epilepsy have shown that CBD may have a specific indication in these forms. Due to its implications in the reward system, endocannabinoid signaling represents a potential therapeutic target in treating addictions. The results from randomized, controlled trials suggest that CB1 receptor agonists such as dronabinol and nabiximols may be effective in treating cannabis withdrawal.
Dronabinol may also decrease opioid withdrawal symptoms. Rimonabant, an inverse agonist of CB1 receptors, has shown promising effects in tobacco cessation; it also causes adverse psychiatric effects. Few clinical trials have examined the effect of cannabinoids in treating alcohol-use disorder; those examining rimonabant have shown negative results. Fourteen studies were found, nine in animals and five in humans.
Some preclinical studies suggest that CBD may have some therapeutic properties in treating opioid-, cocaine-, and psychostimulant-use disorders. Some preliminary data suggest that it could be advantageous in treating cannabis and tobacco-use disorder in humans. One randomized, double -blind clinical trial compared the use of CBD versus amisulpride for 4 weeks in, respectively, 20 and 19 patients with psychosis. A potential advantage for CBD is its milder side effects: The understanding of the relationship between sleep and cannabinoids has been obscured by significant methodological differences resulting in mitigated results.
The results from the literature seem to favor a beneficial effect of acute cannabis intoxication on sleep. On the other hand, regular cannabis use seems to have a negative impact on sleep quality. Different cannabinoids seem to have a differential impact on sleep. One study has suggested a therapeutic potential for dronabinol and nabilone on sleep disorders and nightmares.
Thus, there is preclinical evidence and some clinical evidence for therapeutic properties regarding a number of diseases. However, larger controlled clinical trials are needed to show efficacy and safety for each disorder. Cannabis use and its negative consequences have increased over the last several years in parallel with increasing cannabis potencies. SCs seem to be particularly popular among cannabis users.
This emerging market represents a specific public health problem in light of the severe complications in relation to their use. What the risks are of developing a psychotic disorder after SC administration remains a fundamental question. This is an emerging area of research in which more robust epidemiological studies must be developed. These must provide detailed information concerning not only the quantity and the frequency of cannabis use, but also, and more importantly, the type of cannabis used.
The use of SCs must also be more largely examined in light of the severe consequences associated with their use. The legislative policies that have been established to reduce the risks in relation to cannabis have long represented an obstacle to research concerning medical cannabis use. Improved knowledge of the endocannabinoid system and of exocannabinoids has proven that cannabis may have significant therapeutic effects.
Despite sparse research, certain countries, such as the United States, have authorized the use of plant-based medical cannabis. National Center for Biotechnology Information , U. Journal List Dialogues Clin Neurosci v. Genevieve Lafaye Author affiliations: Laurent Karila Author affiliations: Lisa Blecha Author affiliations: Amine Benyamina Author affiliations: Author information Copyright and License information Disclaimer.
This is an open-access article distributed under the terms of the Creative Commons Attribution License http: Abstract Cannabis also known as marijuana is the most frequently used illicit psychoactive substance in the world. Introduction Cannabis also known as marijuana is a psychoactive plant that contains more than components, of which cannabinoids have presently been identified.
Cannabis today Evolution of THC: CBD ratios Recent reports indicate that cannabis production is increasing and that cannabinoid formulations have been changing over the last two decades, especially with regard to their THC and CBD concentrations. Emerging market of synthetic drugs: Certain serious complications Evolution of THC: CBD ratios and psychosis risk Almost 30 years ago, Andreasson et al showed an association between cannabis use and the later emergence of schizophrenia.
Psychiatric, addictive, and physical consequences of SC use Numerous complications have been observed in SC users. Therapeutic applications of cannabis and cannabinoids THC is the psychoactive principle of cannabis, inducing the cannabis inebriation sought by many users.
Conclusion Cannabis use and its negative consequences have increased over the last several years in parallel with increasing cannabis potencies. Acknowledgments The authors have no conflicts of interest to declare.
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CBD Information – The Ultimate Cannabidiol Information Guide
Aug 4, naturally occurring chemical compounds in the hemp plant. The THC level in Harlequin rarely exceeds 6% while its CBD levels can reach Seed Collective specifically to deliver a higher CBD concentration. When CBD is referred to as full spectrum or whole plant CBD, but in very low concentrations (up to.3%), resulting in very minimal psychoactive stimulation. with full spectrum CBD were provided with higher levels of relief. Although THC and CBD both come from the cannabis plant, it is only THC which It is important to pay attention to the concentration level of the CBD oil you're to purchase a 4 ounce bottle that contained mg of CBD, your concentration.