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Antinociceptive effects of 9α-OH-HHC and 8-OH-iso- HHC in mice

Antinociceptive effects of 9α-OH-HHC and 8-OH-iso- HHC in mice

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Cannabidiol (CBD), a nonpsychoactive cannabinoid, was found to be converted to 9α-hydroxyhexahydrocannabinol (9α-OH-HHC) and 8-hydroxy-iso-hexahydrocannabinol (8-OH-iso-HHC) together with Δ9-tetrahydrocannabinol (Δ9-THC), a psychoactive cannabinoid, and cannabinol in artificial gastric juice. These cannabinoids were identified by gas chromatography...

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... addition to catalepsy, hypothermia, and barbitu- rate synergism, ∆ 9 -THC possesses antinociceptive effects in experimental animals [13,33,34]. Although 9α-OH- HHC and 8-OH-iso-HHC also exhibited an antinocicep- tive effect against the acetic acid-induced writhing test, their effects were much weaker than those of ∆ 9 -THC (Table 2). CBD did not show any signifi cant effect at 10 mg/kg i.v. in these experiments. ...

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... Based on the experiences in our laboratory, some motorists and participants of an abstinence control program claiming to exclusively consume CBD products tested positive for THC or its metabolites. Besides CBD products containing THC, spontaneous conversion of CBD to THC in an acidic environment like simulated gastric fluid has been reported in the literature [11][12][13]. However, results of in vitro experiments have not been consistent in this regard [8]. ...
... The first study describing the conversion of CBD to THC under acidic conditions was reported by Gaoni and Mechoulam in 1965 [11]. Further in vitro investigations of Merrick et al. and Watanabe et al. supported these results using simulated gastric fluid with a pH value of 1.2 at 37 °C [12,13]. Besides the degradation of CBD to ∆ 9 -THC, other cannabinoids such as ∆ 8 -THC and cannabinol (CBN) are formed by adding hydrochloric acid. ...
... Besides the degradation of CBD to ∆ 9 -THC, other cannabinoids such as ∆ 8 -THC and cannabinol (CBN) are formed by adding hydrochloric acid. The conversion rate for ∆ 9 -THC from CBD was 2.9% after 20 h of incubation in the experiments of Wantabe et al. [12]. Even higher conversion rates were reported by Merrick et al. [13] showing that 35% and 25% for ∆ 9 -THC and ∆ 8 -THC, respectively, were formed by CBD degradation after 1 h of incubation. ...
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    Cannabidiol (CBD) products have ascribed an uprising trend for their health-promoting effects worldwide. In contrast to Δ⁹-tetrahydrocannabinol (THC), CBD exhibits no state of euphoria. Since conversion of CBD into THC in an acidic environment has been reported, it has not been proved whether this degradation will also occur in human gastric fluid. A total of 9 subjects ingested 400 mg CBD as a water-soluble liquid together with lecithin as an emulsifier and ethanol as a solubilizer. Blood samples were taken up to 4 h, and urine samples were submitted up to 48 h. THC, 11-hydroxy-Δ⁹-THC (THC-OH), 11-nor-9-carboxy-Δ⁹-THC (THC-COOH), CBD, 7-hydroxy cannabidiol (7-OH-CBD), and 7-carboxy cannabidiol (7-CBD-COOH) were determined in blood and THC-COOH and 7-CBD-COOH in urine by LC–MS/MS. Neither THC, THC-OH, nor THC-COOH were detectable in any serum specimen. Only two urine samples revealed THC-COOH values slightly above the threshold of 10 ng/ml, which could also be caused by trace amounts of THC being present in the CBD liquid. It can be concluded that negative consequences for participants of a drug testing program due to a conversion of CBD into THC in human gastric fluid appear unlikely, especially considering a single intake of dosages of less than 400 mg. Nevertheless, there is a reasonable risk for consumers of CBD products being tested positive for THC or THC metabolites. However, this is probably not caused by CBD cyclization into THC in human gastric fluid but is most likely due to THC being present as an impurity of CBD products.
    ... However, the derivatization process may prevent quantification of easily transforming analytes. A well-described case is just the analysis of CBD and Δ9-THC, which -during derivatization with acid anhydrides [e.g. with trifluoroacetic anhydride (TFAA)]-are easily converted to Δ9-THC and Δ8-THC, and to Δ8-THC [6][7][8][9][10][11], respectively. The amounts of these transformation products are dependent on the reaction conditions (i.e. ...
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    Methods for the analysis of cannabinoids in bio-matrices are continually improved to achieve best possible sensitivity in their detection and accurate quantification. It has been well documented that CBD cyclizes to Δ9-THC and Δ9-THC isomerizes to Δ8-THC under acidic conditions by means of a Lewis-acid-catalyzed process, causing difficulty in accurate quantification of Δ9-THC in the presence of CBD, of CBD itself and of Δ9-THC itself when these compounds have to be derivatized by acylation. The present paper shows that CBD cyclization and Δ9-THC isomerization can be blocked by tertiary amines or azines, which capture protons appearing in the derivatizing mixture during acylation. The efficiency of the described acylation of CBD depends on the time and temperature of the derivatizing process, whereas the degree of CBD acylation, i.e. the synthesis of mono- or di-acylate CBD derivative, depends on the mutual ratio of the cannabinoid, the acylating agent and the proton binding compound. The way of mono- and di-acyl CBD derivatives formation described in the paper has not been reported yet. The paper contains a comprehensive analytical characterization of two types of CBD acyl derivatives, CBD-TFA and CBD-Ac, obtained by NMR, GC–MS and LC–MS.
    ... That said, it is difficult to predict whether the supplement affected oral fluid CBD concentrations as few studies appear to have measured these after oral CBD administration (i.e., providing reference data).One final observation to note is that no oral fluid samples collected in the current study contained detectable levels of THC, CBN or CBG. Indeed, although a small amount of in vitro research suggests that CBD can undergo conversion to THC with prolonged exposure to simulated gastric fluid (e.g., 3-20 h),34,35 several in vivo studies have failed to detect THC in human plasma, 36,37 the blood of rodents and minipigs38,39 and the small intestine and stomach of minipigs 38 following CBD treatment (sometimes at high doses, e.g., 700 mgÁday À1 for 30 days 36 ). The current data add to this body of evidence providing further confirmation that CBD is unlikely to convert to THC, CBN or CBG in oral fluid. ...
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    ... For example, an analytical study of 84 retail CBD products without labeling related to ∆ 9 -THC content detected ∆ 9 -THC in 18 samples with observed ∆ 9 -THC concentrations as high as 6.43 mg/mL (6). Third, in vitro evidence indicates that CBD may degrade to ∆ 8 -and ∆ 9 -THC in simulated gastric fluid of pH = 1.2 (7)(8)(9), suggesting that CBD may be converted to ∆-or ∆ 9 -THC in highly acidic human gastric fluid (pH = 1.0-2.5) (10). ...
    ... In light of in vitro evidence that CBD may degrade to ∆ 8and ∆ 9 -THC in simulated gastric fluid (7)(8)(9), the present study evaluated the potential for conversion of CBD to ∆ 9 -THC or ∆ 8 -THC following acute CBD administration in healthy adults. However, only trace cannabinoids were detected in a few samples, which likely reflect the detection of trace cannabinoids in the placebo cannabis or residual cannabinoids from prior exposure. ...
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    ... For samples 9 to 12, dissolution testing was not performed in FaSSGF solution as the samples shown promising level of CBD release in FaSSIF solution. Few studies suggested the possibility for the conversion of CBD to THC in gastric juice 34,35 and these studies were questioned by the clinical trials conducted by Nahler et al. 36 The study carried out in this paper also proved the concept of Nahler et al. as the chromatograms for samples in FaSSGF not shown any peaks representing THC. The results proved that all hemp oil samples hardly release CBD and not undergoing any conversion to THC in gastric fluid. ...
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    For the first time, a simple and robust HPLC method has been developed for dissolution studies for cannabidiol (CBD) in hemp oil products. An isocratic elution of samples performed on SOLAS™ C18 150 mm x 4.6 mm, 5 μm column with a mobile phase consisting of 75:25 acetonitrile-water v/v, delivered at a flow rate 1.5 mL/minutes to variable wavelength detector using 214 nm. An in-house validated assay test was executed for calculating the purity of hemp oil products and also for considering the dissolution medium to be used. For dissolution studies, equivalent of 5 mg and/or 10 mg of the active was introduced into 500 mL of simulated gastric and intestinal fluids separately, and dissolution was performed at 50 rpm using paddles for 180 minutes. Dissolution profiles for hemp oil products purchased from the United States and Europe were compared. Additionally, dissolution testing was conducted to study the effect of percentage CBD release on increased agitation speed of 75 and 100 rpm and also, on extended dissolution runtime of 240 minutes.
    ... For this reason, athletes must pay particular attention to the source and purity of CBD should they decide to use it. Furthermore, it has been proposed that the sedative effects of CBD may involve some in vivo conversion to THC in the acidic gastric tract (Watanabe et al., 2007), although this remains a matter of dispute (Palazzoli et al., 2018). ...
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    Cannabidiol (CBD) has proven clinical benefits in the treatment of seizures, inflammation, and pain. The recent legalization of CBD in many countries has caused increased interest in the drug as an over-the-counter treatment for athletes looking to improve recovery. However, no data on the effects of CBD on the adaptive response to exercise in muscle are available. To address this gap, we eccentrically loaded the tibialis anterior muscle of 14 rats, injected them with a vehicle ( n = 7) or 100 mg/kg CBD ( n = 7), and measured markers of injury, inflammation, anabolic signaling, and autophagy 18 hr later. Pro-inflammatory signaling through nuclear factor kappa B (NF-kB) (Ser536) increased with loading in both groups; however, the effect was significantly greater (36%) in the vehicle group ( p < .05). Simultaneously, anabolic signaling through ribosomal protein S6 kinase beta-1 (S6K1) (Thr389) increased after eccentric contractions in both groups with no difference between vehicle and CBD ( p = .66). The ribosomal protein S6 phosphorylation (240/244) increased with stimulation ( p < .001) and tended to be higher in the CBD group ( p = .09). The ubiquitin-binding protein p62 levels were not modulated by stimulation ( p = .6), but they were 46% greater in the CBD compared with the vehicle group ( p = .01). Although liver weight did not differ between the groups ( p = .99) and levels of proteins associated with stress were similar, we did observe serious side effects in one animal. In conclusion, an acute dose of CBD decreased pro-inflammatory signaling in the tibialis anterior without blunting the anabolic response to exercise in rats. Future research should determine whether these effects translate to improved recovery without altering adaptation in humans.
    ... The oral route has been associated with possible CBD transformation to THC in the acidic gastric environment suggested by some authors (Figure 3). Such conversion was found in a studies with simulated gastric fluid [59,60]. However, it seems that this conversion does not occur in vivo in humans, as evidenced by the absence of THC in the blood of patients who took even very high doses of CBD orally. ...
    ... Metabolism of cannabidiol[59][60][61][62][63][64][65]67,68]. Abbreviations: 7-COOH-, 7-OH-CBD:7-Carboxy-, 7-hydroxycannabidiol; CBD: Cannabidiol; CYP: Cytochrome P450; p.o.: Per os, orally; s.c.: Subcutaneously; THC: Δ 9 -Tetrahydrocannabinol; UGT: UDP-Glucuronosyltransferase. ...
    ... Metabolism of cannabidiol[59][60][61][62][63][64][65]67,68]. Abbreviations: 7-COOH-, 7-OH-CBD:7-Carboxy-, 7-hydroxycannabidiol; CBD: Cannabidiol; CYP: Cytochrome P450; p.o.: Per os, orally; s.c.: Subcutaneously; THC: ∆ 9 -Tetrahydrocannabinol; UGT: UDP-Glucuronosyltransferase. ...
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    Cannabidiol (CBD) is a non-intoxicating and generally well-tolerated constituent of cannabis which exhibits potential beneficial properties in a wide range of diseases, including cardiovascular disorders. Due to its complex mechanism of action, CBD may affect the cardiovascular system in different ways. Thus, we reviewed the influence of CBD on this system in health and disease to determine the potential risk of cardiovascular side effects during CBD use for medical and wellness purposes and to elucidate its therapeutic potential in cardiovascular diseases. Administration of CBD to healthy volunteers or animals usually does not markedly affect hemodynamic parameters. Although CBD has been found to exhibit vasodilatory and antioxidant properties in hypertension, it has not affected blood pressure in hypertensive animals. Hypotensive action of CBD has been mainly revealed under stress conditions. Many positive effects of CBD have been observed in experimental models of heart diseases (myocardial infarction, cardiomyopathy, myocarditis), stroke, neonatal hypoxic ischemic encephalopathy, sepsis-related encephalitis, cardiovascular complications of diabetes, and ischemia/reperfusion injures of liver and kidneys. In these pathological conditions CBD decreased organ damage and dysfunction, oxidative and nitrative stress, inflammatory processes and apoptosis, among others. Nevertheless, further clinical research is needed to recommend the use of CBD in the treatment of cardiovascular diseases.
    ... The first study reported the formation of THC in 2.9% yield along with other cannabinoid products in artificial gastric fluid without pepsin. 51 In 2016, Zynerba Pharmaceuticals reported the formation of psychoactive cannabinoids (Δ 9 -THC and Δ 8 -THC) by exposing CBD to simulated gastric fluid (SGF), 49 showing 98% conversion of CBD to these THC products (∼49% yield) within 2 h by UPLC−MS analysis ( Figure 5). ...
    Article
    This Miniperspective of the published essential medicinal chemistry of cannabidiol (CBD) provides evidence that the popularization of CBD-fortified or CBD-labelled health products, and associated health claims, lack a rigorous scientific foundation. CBD's reputation as a cure-all puts it in the same class as other “natural” panaceas, where valid ethnobotanicals are reduced to single, purportedly active ingredients. Such reductionist approaches oversimplify useful, chemically complex mixtures in an attempt to rationalize the commercial utility of natural compounds and exploit the “natural” label. Literature evidence associates CBD with certain semi-ubiquitous, broadly-screened, primarily plant-based substances of undocumented purity that interfere with bioassays and have a low likelihood of becoming therapeutic agents. Widespread health challenges and pandemic crises such as SARS-CoV-2 create circumstances under which scientists must be particularly vigilant about healing claims that lack solid foundational data. Herein, we offer a critical review of the published medicinal chemistry properties of CBD, as well as precise definitions of CBD-containing substances and products, distilled to reveal the essential factors that impact its development as a therapeutic agent.
    ... CBD has a similar chemical structure to Δ 9 -THC rendering it plausible that it may be mistakenly identified as Δ 9 -THC on tests relying on specific molecular features. in vitro studies have also shown that CBD can undergo bioconversion to Δ 9 -THC under simulated physiological conditions (Merrick et al., 2016;Watanabe et al., 2007), although this effect has not yet been observed in vivo (Wray, Stott, Jones, & Wright, 2017). In the state of New South Wales (NSW), Australia, roadside drug testing involves an initial test for oral fluid Δ 9 -THC using the Securetec DrugWipe® (DW) device; if positive, a second test is performed using the Dräger DrugTest® 5000 (DT5000). ...
    Article
    Objective Interest in the use of cannabidiol (CBD) is increasing worldwide as its therapeutic effects are established and legal restrictions moderated. Unlike Δ⁹‐tetrahydrocannabinol (Δ⁹‐THC), CBD does not appear to cause cognitive or psychomotor impairment. However, further assessment of its effects on cognitively demanding day‐to‐day activities, such as driving, is warranted. Here, we describe a study investigating the effects of CBD on simulated driving and cognitive performance. Methods Thirty healthy individuals will be recruited to participate in this randomised, double‐blind, placebo‐controlled crossover trial. Participants will complete four research sessions each involving two 30‐min simulated driving performance tests completed 45 and 210 min following oral ingestion of placebo or 15, 300, or 1,500 mg CBD. Cognitive function and subjective drug effects will be measured, and blood and oral fluid sampled, at regular intervals. Oral fluid drug testing will be performed using the Securetec DrugWipe® 5S and Dräger DrugTest® 5000 devices to determine whether CBD increases the risk of “false‐positive” roadside tests to Δ⁹‐THC. Noninferiority analyses will test the hypothesis that CBD is no more impairing than placebo. Conclusion This study will clarify the risks involved in driving following CBD use and assist in ensuring the safe use of CBD by drivers.
    ... In vitro studies have shown that CBD can undergo conversion to Δ 9 -THC with prolonged exposure to simulated gastric fluid [126,189]. However, this effect has not been observed in vivo. ...
    Article
    Full-text available
    Cannabidiol (CBD) is a non-intoxicating cannabinoid derived from Cannabis sativa. CBD initially drew scientific interest due to its anticonvulsant properties but increasing evidence of other therapeutic effects has attracted the attention of additional clinical and non-clinical populations, including athletes. Unlike the intoxicating cannabinoid, Δ9-tetrahydrocannabinol (Δ9-THC), CBD is no longer prohibited by the World Anti-Doping Agency and appears to be safe and well-tolerated in humans. It has also become readily available in many countries with the introduction of over-the-counter "nutraceutical" products. The aim of this narrative review was to explore various physiological and psychological effects of CBD that may be relevant to the sport and/or exercise context and to identify key areas for future research. As direct studies of CBD and sports performance are is currently lacking, evidence for this narrative review was sourced from preclinical studies and a limited number of clinical trials in non-athlete populations. Preclinical studies have observed robust anti-inflammatory, neuroprotective and analgesic effects of CBD in animal models. Preliminary preclinical evidence also suggests that CBD may protect against gastrointestinal damage associated with inflammation and promote healing of traumatic skeletal injuries. However, further research is required to confirm these observations. Early stage clinical studies suggest that CBD may be anxiolytic in "stress-inducing" situations and in individuals with anxiety disorders. While some case reports indicate that CBD improves sleep, robust evidence is currently lacking. Cognitive function and thermoregulation appear to be unaffected by CBD while effects on food intake, metabolic function, cardiovascular function, and infection require further study. CBD may exert a number of physiological, biochemical, and psychological effects with the potential to benefit athletes. However, well controlled, studies in athlete populations are required before definitive conclusions can be reached regarding the utility of CBD in supporting athletic performance.