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Cannabidiol: An overview of some chemical and pharmacological aspects. Part I: Chemical aspects

DOI:10.1016/S0009-3084(02)00144-5
Authors:
Raphael Mechoulam at Hebrew University of Jerusalem
Raphael Mechoulam
Lumir Hanus at School of Pharmacy, Ein Kerem Campus, Hebrew University of Jerusalem
Lumir Hanus
  • School of Pharmacy, Ein Kerem Campus, Hebrew University of Jerusalem
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Abstract and Figures

Over the last few years considerable attention has focused on cannabidiol (CBD), a major non-psychotropic constituent of Cannabis. In Part I of this review we present a condensed survey of the chemistry of CBD; in Part II, to be published later, we shall discuss the anti-convulsive, anti-anxiety, anti-psychotic, anti-nausea and anti-rheumatoid arthritic properties of CBD. CBD does not bind to the known cannabinoid receptors and its mechanism of action is yet unknown. In Part II we shall also present evidence that it is conceivable that, in part at least, its effects are due to its recently discovered inhibition of anandamide uptake and hydrolysis and to its anti-oxidative effect.
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Review
Cannabidiol: an overview of some chemical and
pharmacological aspects. Part I: chemical aspects
Raphael Mechoulam , Lumı´r Hanusˇ
Department of Medicinal Chemistry and Natural Products, Medical Faculty, Hebrew University of Jerusalem, Ein Kerem Campus, 91120
Jerusalem, Israel
Received 15 June 2002; accepted 20 August 2002
Abstract
Over the last few years considerable attention has focused on cannabidiol (CBD), a major non-psychotropic
constituent of Cannabis. In Part I of this review we present a condensed survey of the chemistry of CBD; in Part II, to
be published later, we shall discuss the anti-convulsive, anti-anxiety, anti-psychotic, anti-nausea and anti-rheumatoid
arthritic properties of CBD. CBD does not bind to the known cannabinoid receptors and its mechanism of action is yet
unknown. In Part II we shall also present evidence that it is conceivable that, in part at least, its effects are due to its
recently discovered inhibition of anandamide uptake and hydrolysis and to its anti-oxidative effect.
#2002 Elsevier Science Ireland Ltd. All rights reserved.
Keywords: Cannabidiol; Chemical and pharmacological aspects; Cannabis
1. Introduction
Since the isolation and elucidation of the
structure of the main active constituent of mar-
ijuana, D
9
-tetrahydrocannabinol (THC; Gaoni
and Mechoulam, 1964) an enormous number of
published articles have dealt with its chemistry,
biochemistry, pharmacology and clinical effects.
However, considerable anecdotal evidence has
emerged that the effects of marijuana are not due
to THC alone (Grinspoon and Bakalar, 1997). At
least one constituent, cannabidiol (CBD) was
found to cause a plethora of pharmacological
effects, some of which may modify the metabolism
and effects of THC (see for example Jaeger et al.,
1996; Karniol et al., 1974).
In the present overview we shall try to cover
some aspects of CBD chemistry and its pharma-
cological and clinical effects. It is by no means
exhaustive. The effects of CBD in numerous
systems have been investigated and this short
review is not intended to be of encyclopedic
nature, but mostly expresses the areas of interest
of the authors. The known interactions between
THC and CBD are not presented. They require a
thorough, separate critical evaluation of the lit-
erature, mostly of the 1970’s and 1980’s, based on
Corresponding author. Tel.: /972-2-675-8634; fax: /972-
2-675-7076
E-mail address: mechou@cc.huji.ac.il (R. Mechoulam).
Chemistry and Physics of Lipids 121 (2002) 35 /43
www.elsevier.com/locate/chemphyslip
0009-3084/02/$ - see front matter #2002 Elsevier Science Ireland Ltd. All rights reserved.
PII: S 0 0 0 9 - 3 0 8 4 ( 0 2 ) 0 0 1 4 4 - 5
the new knowledge of cannabinoid receptors and
of CBD effects.
In Part I of this review we present a condensed
survey of the chemistry of CBD; in Part II, to be
published later, we shall discuss the anti-convul-
sive, anti-anxiety, anti-psychotic, anti-nausea and
anti-rheumatoid arthritic properties of CBD.
2. Isolation, structure and absolute stereochemistry
CBD was first isolated from Mexican marijuana
by Roger Adams and from Indian charas by
Alexander Todd, both in 1940. For reviews of
the early work see Adams (1941), Todd (1946).On
the basis of chemical degradation and correlation
with cannabinol, a general structure was proposed.
However, quite surprisingly, for almost 25 years
no further work was reported. In 1963 our group
isolated CBD from Lebanese hashish and estab-
lished its structure and relative stereochemistry, at
positions 3 and 4, mostly on the basis of NMR
measurements (Fig. 1;Mechoulam and Shvo,
1963). A few years later its absolute stereochem-
istry was determined by conversion of CBD into
menthane carboxylic acid of well established
absolute stereochemistry (Mechoulam and Gaoni,
1967;Fig. 1). These early results were of consider-
able importance for the later elucidation of the
structure and stereochemisty of D
9
-THC, the
psychoactive component of Cannabis (Gaoni and
Mechoulam, 1964).
The crystal structure of CBD was determined by
Jones et al. (1977). Two independent forms of this
molecule were noted, which differ mainly in the
conformation of the pentyl side chain. The aro-
matic ring and the terpene ring are almost
perpendicular to each other. The two conformers
are linked by hydrogen bonding of the hydroxyl
moieties.
The chemical nomenclature of CBD differs from
that of THC. While the latter has a pyran ring,
which determines its numbering (see Fig. 1), CBD
has no heterocyclic ring and its numbering stems
from that of the terpene ring. This, somewhat
unfortunate, technicality leads to the same carbon
atom being numbered differently in CBD and
THC.
Fig. 1. Conversion of cannabidiol into D
6
-cannabidiol and degradation to menthane carboxylic acid.
R. Mechoulam, L. Hanusˇ / Chemistry and Physics of Lipids 121 (2002) 35/4336
3. Acid cyclizations of CBD
Acid catalyzed cyclizations within the CBD
molecule take place leading to D
9
-THC and to
iso-THC (Fig. 2) formed from the respective
carbocations on C-8 and C-1 of the CBD skeleton,
respectively (Gaoni and Mechoulam, 1966a, 1968).
The double bond of THC may further isomerize,
leading to D
8
-THC (Gaoni and Mechoulam,
1966b).
While the THC’s, in particular D
9
-THC, have
been thoroughly explored, with thousands of
publications appearing since its establishment as
the major, or essentially the sole psychoactive
Cannabis constituent, the iso-THC’s and its deri-
vatives have received almost no attention.
4. Reactions of CBD under basic conditions
The double bond in CBD on heating with t-
pentyl potassium in toluene-hexamethyl-phospho-
ric triamide undergoes isomerization to the D
6
position, leading to D
6
-CBD (Srebnik et al., 1984;
Fig. 1). Contrary to natural CBD, the D
6
-isomer
showed THC-like activity in rhesus monkeys
Fig. 2. Cyclizations of CBD and related compounds under acidic conditions.
R. Mechoulam, L. Hanusˇ / Chemistry and Physics of Lipids 121 (2002) 35/43 37
(unpublished observations). It should be of con-
siderable interest to compare the conformations of
the two CBD isomers, in order to establish
whether the unexpected difference in activity is
due to a steric change. Recently, Wiley et al. (2002)
prepared and evaluated the binding and some in
vivo effects of a series of bicyclic resorcinols that
resemble CBD. Unlike CBD, most of these
resorcinol derivatives had good activity in binding
to CB
1
and/or CB
2
. The lack of activity of CBD
remains an enigma.
5. Oxidation of CBD and CBD acid
CBD in base in the presence of oxygen is
oxidized to monomeric and dimeric hydroxy-
quinones (Fig. 3). The anions of the oxidized
compounds have a deep violet color (Mechoulam
et al., 1968). This is the basis of the Beam reaction
used for identification of Cannabis.
Oxidation of CBD diacetate with selenium
dioxide leads mainly to the aldehyde on the C-10
position (Fig. 4), with no oxidation of the C-7
position as seen with THC (Lander et al., 1976).
However, oxidation with sodium chromate takes
place on the C-6 position (Lander et al., 1976).
An alternative entry to substitution at C-10 of
CBD was reported (Jorapur et al., 1985), using the
10-bromo-CBD acetate obtained by treatment of
CBD diacetate with N-bromosuccinimide (Jora-
pur et al., 1984).
Cannabidiolic acid methyl ester on oxidation
with manganese dioxide gave mainly the epimers
of the methyl esters of the naturally occurring
cannabielsoic acid (Shani and Mechoulam, 1970).
This reaction could be significantly improved on
bubbling of oxygen, which presumably reactivated
the manganese dioxide (Fig. 5).
The same reaction took place without manga-
nese dioxide by oxidative cyclization in the pre-
sence of air under irradiation (Fig. 5,Shani and
Mechoulam, 1970, 1974).
Most of these CBD derivatives were prepared
before the biological properties of CBD were
discovered and their evaluation may lead to novel
therapeutic leads.
6. Photochemical reactions of CBD
In a review of the pharmacological work of his
group Loewe mentions that ‘‘... unwirksamen
Cannabidiol wurde nach Ultraviolet-bestrahlung
ein wirkstoffgehalt nachgewiesen ...’’, but this
work was never reported in detail (Loewe, 1950).
We have found that irradiation of CBD in
methanol with a 450 W lamp in a Corex vessel
gave a mixture from which mainly isomeric 1-
methoxy dihydro CBD’s were obtained (Shani and
Mechoulam, 1971). However, irradiation in cyclo-
hexane led to the formation of some THC, in
addition to iso-THC, reduced CBD and the
addition product of cyclohexane to CBD, giving
cyclohexyl CBD (Fig. 6). These reactions indicate
that CBD is photoreactive and should be guarded
from light when stored.
7. Synthesis of CBD
Several syntheses of CBD have been reported.
The most efficient one apparently is the acid
condensation of p-mentha-2,8-dien-1-ol with oli-
Fig. 3. Quinone formation from CBD.
R. Mechoulam, L. Hanusˇ / Chemistry and Physics of Lipids 121 (2002) 35/4338
vetol, as originally proposed by Petrzilka et al.
(1967) and later improved by Baek et al., (1985)
(Fig. 7). The yield reported (41% of crystalline
material) in this one step reaction makes CBD
readily available.
8. Metabolism of CBD
The metabolism of CBD is well established. In
numerous species, including man, the first step is
hydroxylation, mostly on C-7, leading to 7-hy-
droxy-CBD, followed by further oxidations, lead-
ing to CBD-7-oic acid, and numerous
hydroxylated derivatives of this acid (Fig. 8,
Harvey and Mechoulam, 1990; Harvey et al.,
1991). Glucuronides of these oxidized metabolites
are also formed (for a review see Agurell et al.,
1986).
The syntheses of both 7-hydroxy-CBD (Tchili-
bon and Mechoulam, 2000) and of CBD-7-oic acid
(unpublished) have recently been achieved (Fig. 9).
Fig. 4. Oxidations of CBD diacetate.
Fig. 5. Formation of cannabelsoic acid-type compounds from CBD.
R. Mechoulam, L. Hanusˇ / Chemistry and Physics of Lipids 121 (2002) 35/43 39
Fig. 6. Photochemical reactions of CBD.
Fig. 7. Synthesis of CBD.
R. Mechoulam, L. Hanusˇ / Chemistry and Physics of Lipids 121 (2002) 35/4340
9. CBD chemistry: a summary
The chemistry of CBD has been well explored
over the last 35 years. In view of the various,
potentially therapeutic, effects caused by CBD, it
seems plausible that novel synthetic approaches
will be developed in the future to lead to new types
of derivatives.
Fig. 8. Metabolites of CBD.
R. Mechoulam, L. Hanusˇ / Chemistry and Physics of Lipids 121 (2002) 35/43 41
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... The pharmacokinetic parameters of ∆ 9 -THC vary based on the administration route [26]. If ∆ 9 -THC is administered through inhalation, the majority is absorbed through the lungs [21,26], which leads to fast entry into the bloodstream, quick reach to the brain, and the onset of psychoactive or soothing effects within seconds to a few minutes [21,26]. Smoked ∆ 9 -THC has a tmax of 3-10 min and a Cmax of approximately 150 ng/mL, with a bioavailability of 10-35% in plasma [21]. ...
... The pharmacokinetic parameters of ∆ 9 -THC vary based on the administration route [26]. If ∆ 9 -THC is administered through inhalation, the majority is absorbed through the lungs [21,26], which leads to fast entry into the bloodstream, quick reach to the brain, and the onset of psychoactive or soothing effects within seconds to a few minutes [21,26]. Smoked ∆ 9 -THC has a tmax of 3-10 min and a Cmax of approximately 150 ng/mL, with a bioavailability of 10-35% in plasma [21]. ...
... Smoked ∆ 9 -THC has a tmax of 3-10 min and a Cmax of approximately 150 ng/mL, with a bioavailability of 10-35% in plasma [21]. If ∆ 9 -THC is administered through oral ingestion, it undergoes two metabolisms in the liver [26]. In this case, ∆ 9 -THC reaches its maximum concentration of 58 ng/mL in plasma slowly, with a tmax of 1-2 h and even 6 h in some cases [26]. ...
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Chronic pain is now included in the designation of chronic diseases, such as cancer, diabetes, and cardiovascular disease, which can impair quality of life and are major causes of death and disability worldwide. Pain can be treated using cannabinoids such as Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) due to their wide range of therapeutic benefits, particularly as sedatives, analgesics, neuroprotective agents, or anti-cancer medicines. While little is known about the pharmacokinetics of these compounds, there is increasing interest in the scientific understanding of the benefits and clinical applications of cannabinoids. In this review, we study the use of nanomaterial-based electrochemical sensing for detecting Δ9-THC and CBD. We investigate how nanomaterials can be functionalized to obtain highly sensitive and selective electrochemical sensors for detecting Δ9-THC and CBD. Additionally, we discuss the impacts of sensor pretreatment at fixed potentials and physiochemical parameters of the sensing medium, such as pH, on the electrochemical performance of Δ9-THC and CBD sensors. We believe this review will serve as a guideline for developing Δ9-THC and CBD electrochemical sensors for point-of-care applications.
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... At both temperatures, the extracted CBD from the PVA matrix shows a significant change in the main bands between 2800-3100 cm −1 , 1400-1800 cm −1 and at 1060 cm −1 during the time studied [27]. There is a loss in the strength of the vinyl stretching band at 3070 cm −1 after 1 week of storage at both temperatures, which is observed in previous studies [35]. The stability of the (C-C-H) aliphatic moiety (1360 cm −1 ) and the aromatic C-OH vibration (1200 cm −1 ) is preserved for a longer time at 4 °C than at 40 °C with 60% humidity. ...
... At both temperatures, the extracted CBD from the PVA matrix shows a significant change in the main bands between 2800-3100 cm −1 , 1400-1800 cm −1 and at 1060 cm −1 during the time studied [27]. There is a loss in the strength of the vinyl stretching band at 3070 cm −1 after 1 week of storage at both temperatures, which is observed in previous studies [35]. The stability of the (C-C-H) aliphatic moiety (1360 cm −1 ) and the aromatic C-OH vibration (1200 cm −1 ) is preserved for a longer time at 4 • C than at 40 • C with 60% humidity. ...
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... Entrando en el año 1930 se sanciona la Marihuana Tax Act, que criminalizaba la venta como delito federal en los EE.UU.. Se estableció el consumo de Cannabis como inductor de la violencia, en determinados grupos minoritarios de la sociedad, como bohemios, músicos de jazz, marinos, inmigrantes mexicanos. Se ha planteado que esta restricción fue implementada con el fin de recaudar más impuestos (Musto, 1991 (Mechoulam & Hanuš, 2002). Presenta propiedades hidrofóbicas (alta solubilidad en lípidos), por vía intravenosa debe administrarse disuelto en alcohol en una solución salina. ...
... En estas décadas las investigaciones se volcaron a estudios clínicos controlados para evaluar sus efectos y toxicidad potencial del consumo a gran escala de esta planta(Noyes & Baram, 1974;Mikuriya, 1969).En este periodo hubo una proliferación de estudios sobre los componentes activos de la planta de Cannabis, fenómeno que puede relacionarse al aumento en el porcentaje de publicaciones en revistas categorizadas en el sub-área temática de la neurociencia (en idioma inglés: -neuroscience‖). Esto también puede relacionarse a la identificación, en el año 1964, de la estructura química de Δ9-tetrahidrocannabinol (THC) mediante las investigaciones de Mechoulam y Gaoni(Mechoulam 1970;Mechoulam & Hanuš, 2002), principal componente psicoactivo que posee la planta. El conocimiento de las estructuras químicas, que hizo posible la obtención de sus componentes puros, contribuyó a un aumento significativo en el interés científico sobre el Cannabis. ...
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... Cannabidiol (CBD) is a non-psychoactive phytocannabinoid (Figure 1), the second major active component in the Cannabis sativa L. plant [3]. CBD has been studied in association with a wide range of ailments, due to its multiple therapeutic effects together with good safety profile and the lack of psychotropic activity [5][6][7][8]. It possesses strong anti-inflammatory activities as well as having anti-epileptic, anti-emetic, anti-psychotic and anti-convulsive effects [1,6,[9][10][11]. ...
... CBD has been studied in association with a wide range of ailments, due to its multiple therapeutic effects together with good safety profile and the lack of psychotropic activity [5][6][7][8]. It possesses strong anti-inflammatory activities as well as having anti-epileptic, anti-emetic, anti-psychotic and anti-convulsive effects [1,6,[9][10][11]. Due to that, CBD was found beneficial in treatment of various diseases including cancer, inflammatory, neurodegenerative, autoimmune and cardiovascular diseases [1,5,7,12]. ...
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... CBD is a terpene phenol molecule with 21 carbon atoms, the formula C 21 H 30 O 2 , and a molecular weight of 314.464 g/mol [24]. Chemically, CBD is 2-(1R-3-methyl-6R-[1-methylethenyl]-2-cyclo hexen-1-yl)-5-pentyl-1,3-benzenediol and was described in 1963 [25,26]. Adams [27] and Todd [28] were the first to extract CBD from Mexican marijuana and Indian charas in 1940. ...
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Article
  • Mar 2023
Cannabidiol (CBD), a nonpsychotropic phytocannabinoid that was once largely disregarded, is currently the subject of significant medicinal study. CBD is found in Cannabis sativa, and has a myriad of neuropharmacological impacts on the central nervous system, including the capacity to reduce neuroinflammation, protein misfolding and oxidative stress. On the other hand, it is well established that CBD generates its biological effects without exerting a large amount of intrinsic activity upon cannabinoid receptors. Because of this, CBD does not produce undesirable psychotropic effects that are typical of marijuana derivatives. Nonetheless, CBD displays the exceptional potential to become a supplementary medicine in various neurological diseases. Currently, many clinical trials are being conducted to investigate this possibility. This review focuses on the therapeutic effects of CBD in managing neurological disorders like Alzheimer’s disease, Parkinson’s disease and epilepsy. Overall, this review aims to build a stronger understanding of CBD and provide guidance for future fundamental scientific and clinical investigations, opening a new therapeutic window for neuroprotection.
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... [34]. However, the conversion does not occur from the heat during smoking, nor has it been observed in vivo [35,36]. ...
A Review on the Impact of Cannabis in Society and the Analytical Methodologies for Cannabinoids
Article
Full-text available
  • Feb 2023
The use of plant-based medicine dates back centuries, and cannabis (Cannabis sativa) is one such plant that has been used medicinally and illicitly. Although cannabis contains hundreds of cannabinoids and other natural products, its potential medicinal use was largely ignored by modern researchers due to the legal restrictions and heavy regulations introduced in the 1930s. As restrictions on cannabis access have eased since the 1990s there is renewed interest in the research of cannabinoids and the other components in the cannabis plant. The focus of this review article is an overview of cannabis and the analytical challenges in the quality control and biological analysis. The pharmacological effects of psychoactive cannabinoids, delta-9-tetrahydrocannabinol (Δ9-THC) and delta-8-trans- tetrahydrocannabinol (Δ8-THC) is discussed, along with an abundant non-intoxicating cannabinoid, cannabidiol (CBD). The analytical methods for the quality control assays of cannabis products include gas chromatography and liquid chromatography coupled to different detectors, including mass spectrometry. This review will highlight various analytical methods for the quality control of cannabis products and the quantitation of cannabinoids in biological matrices for forensics and toxicology.
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... Cannabidiol (CBD), which is found in Cannabis sativa, contains about 80 cannabinoids [14]. CBD, as a nonpsychoactive compound, is used to treat neuropathic pain, cancer, and inflammation [15][16][17]. The effects of CBD on gynecologic disorders have been discussed in the literature. ...
Treatment of Ovarian Hyperstimulation Syndrome in a Mouse Model by Cannabidiol, an Angiogenesis Pathway Inhibitor
Article
Full-text available
Studies suggest that ovarian hyperstimulation syndrome (OHSS) can be treated by reducing the level of vascular endothelial growth factor (VEGF). However, due to the side effects of commercially available VEGF-reducing drugs, they can be ruled out as a suitable treatment for OHSS; therefore, researchers are looking for new medications to treat OHSS. This study is aimed at investigating the effects of cannabidiol (CBD) in an OHSS model and to evaluate its efficacy in modulating the angiogenesis pathway and VEGF gene expression. For this purpose, 32 female mice were randomly divided into four groups (eight mice per group): control group, group 2 with OHSS induction, group 3 receiving 32 nmol of dimethyl sulfoxide after OHSS induction, and group 4 receiving 30 mg/kg of CBD after OHSS induction. The animals’ body weight, ovarian weight, vascular permeability (VP), and ovarian follicle count were measured, and the levels of VEGF gene and protein expression in the peritoneal fluid were assessed. Based on the results, CBD decreased the body and ovarian weights, VP, and corpus luteum number compared to the OHSS group ( p < 0.05 ). The peritoneal VEGF gene and protein expression levels reduced in the CBD group compared to the OHSS group ( p < 0.05 ). Also, CBD caused OHSS alleviation by suppressing VEGF expression and VP. Overall, CBD downregulated VEGF gene expression and improved VP in OHSS.
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... Among them, the most well-studied pharmacologically active ingredients are cannabinoids, and in Cannabis, 90 cannabinoids have been identified and characterized so far [5,6]. The predominant cannabinoids, including ∆9-tetrahydrocannabinol (∆9-THC), a psychotropic compound, and cannabidiol (CBD), with neuroprotective properties, are well-studied secondary metabolites produced in Cannabis plants [7,8]. Cannabis plants are of two types: marijuana and hemp. ...
Profiling Cannabinoid Contents and Expression Levels of Corresponding Biosynthetic Genes in Commercial Cannabis (Cannabis sativa L.) Cultivars
Article
Full-text available
  • Nov 2022
Cannabis (Cannabis sativa L.) is widely cultivated and studied for its psychoactive and medicinal properties. As the major cannabinoids are present in acidic forms in Cannabis plants, non-enzymatic processes, such as decarboxylation, are crucial for their conversion to neutral active cannabinoid forms. Herein, we detected the levels of cannabidivarin (CBDV), cannabidiol (CBD), cannabichromene (CBC), and Δ9-tetrahydrocannabinol (Δ9-THC) in the leaves and vegetative shoots of five commercial Cannabis cultivars using a combination of relatively simple extraction, decarboxylation, and high-performance liquid chromatography analyses. The CBDV, CBC, and Δ9-THC levels were 6.3–114.9, 34.4–187.2, and 57.6–407.4 μg/g, respectively, and the CBD levels were the highest, ranging between 1.2–8.9 μg/g in leaf and vegetative shoot tissues of Cannabis cultivars. Additionally, correlations were observed between cannabinoid accumulation and transcription levels of genes encoding key enzymes for cannabinoid biosynthesis, including CsCBGAS, CsCBDAS, CsCBCAS, and CsTHCAS. These data suggest that the high accumulation of cannabinoids, such as CBC, Δ9-THC, and CBD, might be derived from the transcriptional regulation of CsCBGAS and CsCBDAS in Cannabis plants.
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Cannabidiol improves Nile tilapia cichlid fish welfare
Article
Full-text available
  • Oct 2022
Cannabidiol (CBD) is a substance derived from Cannabis sativa, widely studied in medicine for controlling neural diseases in humans. Besides the positive effects on humans, it also presents anxiolytic proprieties and decreases aggressiveness and stress in mammals. Therefore, CBD has the potential to increase welfare in reared animals, as it seems to reduce negative states commonly experienced in artificial environments. Here, we tested the effect of different CBD doses (0, 1, 10 and 20 mg/kg) on aggressiveness, stress and reproductive development of the Nile tilapia (Oreochromis niloticus) a fish reared worldwide for farming and research purposes. CBD mixed with fish food was offered to isolated fish for 5 weeks. The 10 mg/kg dose decreased fish’s aggressiveness over time, whereas 20 mg/kg attenuated non-social stress. Both doses decreased the baseline cortisol level of fish and increased the gonadosomatic index. However, CBD 1 and 10 mg/kg doses decreased the spermatozoa number. No CBD dose affected feeding ingestion and growth variables, showing that it is not harmful to meat production amount. Despite the effect on spermatozoa, CBD supplementation exhibits high potential to benefit animals’ lives in artificial environments. Therefore, we showed for the first time that CBD could be used as a tool to increase non-mammal welfare, presenting a great potential to be explored in other husbandry and captivity species.
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Cannabielsoic acids : Isolation and synthesis by a novel oxidative cyclization
Article
Full-text available
Two tricyclic dihydrobenzofuran cannabinoids, cannabielsoic acids A (4a) and B (5a) were isolated from hashish. Their structures were elucidated by chemical transformations and from spectral data. Cannabielsoic acid A was synthesized from cannabidiolic acid by an oxidative cyclization in the presence of air under irradiation, or with manganese dioxide.
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A new type of cannabinoid. Synthesis of cannabielsoic acid A by a novel photo-oxidative cyclisation
Article
Full-text available
Two tricyclic dihydrobenzofuran cannabinoids have been isolated and one of them has been synthesized by an intramolecular photo-oxidative cyclisation which involves attack by a phenoxy-group and molecular oxygen on a double bond.
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ChemInform Abstract: BORON TRIFLUORIDE ETHERATE ON ALUMINA - A MODIFIED LEWIS ACID REAGENT. AN IMPROVED SYNTHESIS OF CANNABIDIOL
Article
  • Jul 1985
An Aluminiumoxid adsorbiertes Bortrifluoridetherat katalysiert die Kondensation von Resorcin und Resorcin-Derivaten mit Monoterpen-Allylalkoholen.
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The ISO-Tetrahydrocannabinols
Article
Synthetic routes are described which lead to iso-tetrahydrocannabinols, a new series of structural isomers of the natural Δ1-tetrahydrocannabinol. In this group of compounds a dihydrobenzopyran ring system is formed by cyclization of one of the phenolic groups of a cannabinoid with the C1 carbon in the terpene moiety of the molecule.
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Boron triflouride etherate on alimina - a modified Lewis acid reagent. An improved synthesis of cannabidiol
Article
Boron trifluoride etherate on alumina catalyses the condensation of resorcinols an monomethyl resorcinols with several monoterpenoid allylic alcohols: in contrast to parallel reactions with boron trifluoride etherate in solution the products obtained do not undergo further cyclisations.
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Hashish-VII. The isomerization of cannabidiol to tetrahydrocannabinols
Article
Depending on the reaction conditions used, the physiologically active products obtained by Adams on isomerization of the inactive cannabidiol (Ia) with acids are shown to be either Δ1(6) tetrahydrocannabinol (II) or a mixture of II, Δ1 tetrahydrocannabinol (IIIa) and the two isomers of 1-ethoxy hexahydrocannabinol (VIIIa, VIIIb).
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Resorcinol Derivatives: A Novel Template for the Development of Cannabinoid CB1/CB2 and CB2Selective Agonists
Article
  • May 2002
The role of the oxygen of the benzopyran substituent of Δ9-tetrahydrocannabinol in defining affinity for brain cannabinoid (CB1) receptors is not well understood; however, it is known that opening the pyran ring can result in either increased potency and affinity, as in CP 55,940 [(−)- cis- 3-[2-hydroxy-4(1,1- dimethyl-heptyl)phenyl]- trans- 4-(3-hydroxy-propyl)cyclohexanol], or in an inactive cannabinoid, as in cannabidiol. In the present study, a series of bicyclic resorcinols that resemble cannabidiol were synthesized and tested in vitro and in vivo. Analysis of the structure-activity relationships of these analogs revealed several structural features that were important for maintaining CB1receptor recognition and in vivo activity, including the presence of a branched lipophilic side chain and free phenols as well as substitution of a cyclohexane as the second ring of these bicyclic cannabinoids. Many of these analogs exhibited CB2 selectivity, particularly the dimethoxyresorcinol analogs, and this selectivity was enhanced by longer side chain lengths. Hence, unlike cannabidiol, these resorcinol derivatives had good affinity for CB1 and/or CB2 receptors as well as potent in vivo activity. These results suggest that the resorcinol series represent a novel template for the development of CB2-selective cannabinoid agonists that have the potential to offer insights into similarities and differences between structural requirements for receptor recognition at CB1 and CB2 receptors.
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