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by Are Cannabinoid Pharmacokinetics Metabolism Driven



  • by Are Cannabinoid Pharmacokinetics Metabolism Driven
  • CYP3A4 Genetics – Importance For THC & CBD Metabolism
  • 2. Pharmacokinetics of Cannabinoids
  • Cannabinoid pharmacokinetics research is challenging due to low analyte concentrations, rapid and extensive metabolism, and physico-chemical. [Tetrahydrocannabinol pharmacokinetics; new synthetic cannabinoids; road the culture medium led to a dramatic drop of mitochondrial oxidative metabolism . The enzyme CYP3A4 can metabolize both THC and CBD. Its *22 Cannabinoid Pharmacokinetics Are Driven by Metabolism. It is a myth that.

    by Are Cannabinoid Pharmacokinetics Metabolism Driven

    This constellation self emulsifies into nano particles that entrap the cannabinoids and the piperine in their core and thus improve their solubility while piperine and the other PNL excipients inhibit their intestinal metabolism.

    Another clear advantage of the formulation is that its composition of materials is approved for human consumption. The safe nature of the excipients enabled their direct evaluation in humans. The trial comprised of 9 healthy volunteers under fasted conditions. Single oral administration of the piperine-PNL formulation resulted in a 3-fold increase in Cmax and a 1.

    For CBD, a 4-fold increase in Cmax and a 2. These findings demonstrate the potential this formulation has. Cannabinoids induce incomplete maturation of cultured human leukemia cells.

    Monocyte maturation markers were induced in cultured human myeloblastic ML-2 leukemia cells after treatment for days with 0. After a 2-day or longer treatment, 2- to 5-fold increases were found in the percentages of cells exhibiting reactivity with either the murine OKM1 monoclonal antibody of the Leu-M5 monoclonal antibody, staining positively for nonspecific esterase activity, and displaying a promonocyte morphology. The increases in these differentiation markers after treatment with 0.

    M THC were dose dependent. At this dose range, THC did not cause an inhibition of cell growth. The THC-induced differentiation did not, however, result in cells with a highly developed mature monocyte phenotype. However, treatment of these incompletely matured cells with either phorbol myristate acetate of The ML-2 cell system described here may be a useful tool for deciphering critical biochemical events that lead to the cannabinoid -induced incomplete cell differentiation of ML-2 cells and other related cell types.

    Findings obtained from this system may have important implications for studies of cannabinoid effects on normal human bone-marrow progenitor cells. Identification of Recent Cannabis Intake. Additionally, while smoking is the most common administration route, vaporization and edibles are frequently used. We characterized blood pharmacokinetics of THC, its phase I and phase II glucuronide metabolites, and minor cannabinoids in occasional and frequent cannabis smokers for 54 occasional and 72 frequent hours after controlled smoked, vaporized, and oral cannabis administration.

    CBG and CBN were frequently identified after inhalation routes with short detection windows, but not detected following oral dosing. CBG and CBN are recent-use cannabis markers after cannabis inhalation, but their absence does not exclude recent use. Multiple, complimentary criteria should be implemented in conjunction with impairment observations to improve interpretation of cannabinoid tests.

    Implications for Future Therapies. Cannabinoids have shown to reduce joint damage in animal models of arthritis and reduce matrix metalloproteinase expression in primary human osteoarthritic OA chondrocytes. However, to date very few studies have investigated the expression and localization of these receptors in human chondrocytes, and expression during degeneration, and thus their potential in clinical applications is unknown.

    Human articular cartilage from patients with symptomatic OA was graded histologically and the expression and localization of cannabinoid receptors within OA cartilage and underlying bone were determined immunohistochemically.

    Expression levels across regions of cartilage and changes with degeneration were investigated. Conversely, the number of chondrocytes within the deep zone of cartilage displaying immunopositivity for GPR18 and TRPV1 was significantly decreased in degenerate cartilage. Receptor expression was higher in chondrocytes than in osteocytes in the underlying bone.

    Chondrocytes from OA joints were shown to express a wide range of cannabinoid receptors even in degenerate tissues, demonstrating that these cells could respond to cannabinoids. Cannabinoids designed to bind to receptors inhibiting the catabolic and pain pathways within the arthritic joint, while avoiding psychoactive effects, could provide potential arthritis therapies. A review of oral cannabinoids and medical marijuana for the treatment of chemotherapy-induced nausea and vomiting: A PubMed search of the English-language literature available through 4 January was conducted to identify relevant articles for inclusion in the review.

    A new oral dronabinol solution has decreased intraindividual variability area under the curve vs oral dronabinol capsules. The PD profile e. Oral cannabinoids are associated with greater incidence of adverse effects compared with conventional antiemetic therapy or placebo e.

    A new formulation of oral cannabinoids i. Plasma cannabinoid pharmacokinetics following controlled oral delta9-tetrahydrocannabinol and oromucosal cannabis extract administration. Cannabis smokers provided written informed consent to participate in this randomized, controlled, double-blind, double-dummy institutional review board-approved study.

    Participants received 5 and 15 mg synthetic oral THC, low-dose 5. Nine cannabis smokers completed all 5 dosing sessions. Significant differences P pharmacokinetic interaction at these therapeutic doses. METHODS Cannabis smokers provided written informed consent to participate in this randomized, controlled, double-blind, double-dummy institutional review board—approved study.

    The behavioral profile of spice and synthetic cannabinoids in humans. The use of synthetic cannabinoids spice is increasing. The number of descriptions of new clinical side effects is also increasing. We screened relevant publications for articles about spice with a focus on the clinical manifestations of the use of this drug. Spice creates diffuse psychiatric and somatic effects that are only partially similar to those of natural cannabinoids. Most of the observed effects are related to sympathomimetic-cardiac effects and neuropsychiatric manifestations.

    Clinical treatment is primarily based on intensive apparative and laboratory monitoring and supportive therapy. Because the exact active ingredients of spice are often difficult to determine with standard specific toxicology testing, the assessment and analysis of consumed substances by specialized laboratories is recommended.

    Genetic variability in the human cannabinoid receptor 1 is associated with resting state EEG theta power in humans. It has long been postulated that exogenous cannabinoids have a profound effect on human cognitive functioning. These cannabinoid effects are thought to depend, at least in parts, on alterations of phase-locking of local field potential neuronal firing.

    The latter can be measured as activity in the theta frequency band Hz by electroencephalogram. Theta oscillations are supposed to serve as a mechanism in neural representations of behaviorally relevant information.

    However, it remains unknown whether variability in endogenous cannabinoid activity is involved in theta rhythms and therefore, may serve as an individual differences index of human cognitive functioning. To assess variability in the endocannabinoid system, two genetic polymorphisms rs, rs within the cannabinoid receptor 1 CB1 were determined in all participants.

    As expected, we observed significant effects of rs on EEG power in the theta band at frontal, central and parietal electrode regions. Crucially, these effects were specific for the theta band, with no effects on activity in the other frequency bands. Rs showed no significant associations with theta power after Bonferroni correction. Taken together, we provide novel evidence in humans showing that genetic variability in the cannabinoid receptor 1 is associated with resting state EEG power in the theta frequency band.

    This extends prior findings of exogenous cannabinoid effects on theta power to the endogenous cannabinoid system. Genetic variations in the human cannabinoid receptor gene are associated with happiness. Happiness has been viewed as a temporary emotional state e. As previous studies demonstrated that individuals with high subjective happiness level rated their current affective states more positively when they experience positive events, these two aspects of happiness are interrelated.

    According to a recent neuroimaging study, the cytosine to thymine single-nucleotide polymorphism of the human cannabinoid receptor 1 gene is associated with sensitivity to positive emotional stimuli. Thus, we hypothesized that our genetic traits, such as the human cannabinoid receptor 1 genotypes, are closely related to the two aspects of happiness.

    In Experiment 1, healthy volunteers were used to compare the subjective happiness level between cytosine allele carriers and thymine-thymine carriers of the human cannabinoid receptor 1 gene. In Experiment 2, we used positron emission tomography with 20 healthy participants to compare the brain responses to positive emotional stimuli of cytosine allele carriers to that of thymine-thymine carriers.

    Compared to thymine-thymine carriers, cytosine allele carriers have a higher subjective happiness level. Regression analysis indicated that the cytosine allele is significantly associated with subjective happiness level. The positive mood after watching a positive film was significantly higher for the cytosine allele carriers compared to the thymine-thymine carriers. Positive emotion-related brain region such as the medial prefrontal cortex was significantly activated when the cytosine allele carriers watched the positive film compared to the thymine-thymine carriers.

    Thus, the human cannabinoid receptor 1 genotypes are closely related to two aspects of happiness. Compared to thymine-thymine carriers, the cytosine allele carriers of the human cannabinoid receptor 1 gene, who are sensitive to positive emotional stimuli, exhibited greater magnitude.

    Human metabolites of synthetic cannabinoids JWH and JWH bind with high affinity and act as potent agonists at cannabinoid type-2 receptors. Preliminary evidence of cannabinoid effects on brain-derived neurotrophic factor BDNF levels in humans.

    Background Acute and chronic exposure to cannabinoids has been associated with cognitive deficits, a higher risk for schizophrenia and other drug abuse. However, the precise mechanism underlying such effects is not known.

    Preclinical studies suggest that cannabinoids modulate brain-derived neurotrophic factor BDNF. Further, light users of cannabis had lower basal BDNF levels. Implications The effects of socially relevant doses of cannabinoids on BDNF suggest a possible mechanism underlying the consequences of exposure to cannabis. This may be of particular importance for the developing brain and also in disorders believed to involve altered neurodevelopment such as schizophrenia.

    Larger studies to investigate the effects of cannabinoids on BDNF and other neurotrophins are warranted. Antitumor effects of cannabidiol, a nonpsychoactive cannabinoid , on human glioma cell lines. Recently, cannabinoids CBs have been shown to possess antitumor properties. Because the psychoactivity of cannabinoid compounds limits their medicinal usage, we undertook the present study to evaluate the in vitro antiproliferative ability of cannabidiol CBD , a nonpsychoactive cannabinoid compound, on U87 and U human glioma cell lines.

    The addition of CBD to the culture medium led to a dramatic drop of mitochondrial oxidative metabolism [3- 4,5-dimethylthiazolyl -2,5-diphenyl-2H tetrazolium bromide test] and viability in glioma cells, in a concentration-dependent manner that was already evident 24 h after CBD exposure, with an apparent IC 50 of 25 microM.

    The antiproliferative effect of CBD was partially prevented by the CB2 receptor antagonist N-[ 1S -endo-1,3,3-trimethylbicyclo[2,2,1]heptanyl] 4-chloromethylphenyl 4-methylbenzyl -pyrazolecarboxamide SR; SR2 and alpha-tocopherol. By contrast, the CB1 cannabinoid receptor antagonist N- piperidinyl 4-chlorophenyl 2,4-dichlorophenyl methyl-1H-pyrazolecarboximide hydrochloride SR; SR1 , capsazepine vanilloid receptor antagonist , the inhibitors of ceramide generation, or pertussis toxin did not counteract CBD effects.

    We also show, for the first time, that the antiproliferative effect of CBD was correlated to induction of apoptosis, as determined by cytofluorimetric analysis and single-strand DNA staining, which was not reverted by cannabinoid antagonists. Finally, CBD, administered s. In conclusion, the nonpsychoactive CBD was able to produce a significant antitumor activity both in vitro and in vivo, thus suggesting a possible application of CBD as an antineoplastic agent.

    The effects of cannabinoids on serum cortisol and prolactin in humans. Background Cannabis is one of the most widely used illicit substances, and there is growing interest in the therapeutic applications of cannabinoids.

    While known to modulate neuroendocrine function, the precise acute and chronic dose-related effects of cannabinoids in humans are not well-known. Frequent users also had lower baseline plasma prolactin levels relative to healthy controls. Conclusions These group differences may be related to the development of tolerance to the neuroendocrine effects of cannabinoids. Alternatively, these results may reflect inherent differences.

    Excretion, metabolism, and pharmacokinetics of CP,, a selective cannabinoid receptor antagonist, in rats, mice, and dogs. In this study, we investigated the metabolic fate and disposition of CP, in rats, Tg-RasH2 mice, and dogs after oral administration of a single dose of [ 14 C]CP, Total mean recoveries of the radioactive dose were The major route of excretion in all three species was via the feces, but on the basis of separate studies in bile duct-cannulated rats and dogs, this probably reflects excretion in bile rather than incomplete absorption.

    CP, underwent extensive metabolism in all three species, because no unchanged parent compound was detected in the urine across species. The primary metabolic pathway of CP, involved N-deethylation to form an N-desethyl metabolite M1. M1 was subsequently metabolized by amide hydrolysis, oxidation, and ribose conjugation to numerous novel and unusual metabolites.

    The major circulating and excretory metabolites were species-dependent; however, several common metabolites were observed in more than one species. Gender-related differences were also apparent in the quantitative and qualitative nature of the metabolites in rats. An unprecedented metabolite, M4, formed by deamidation of M1 or M3 N-hydroxy-M1 , but not by decarboxylation of M2, was identified in all species.

    M4 was nonenzymatically converted to M5. Failure to extinguish fear and genetic variability in the human cannabinoid receptor 1. Failure to extinguish fear can lead to persevering anxiety and has been postulated as an important mechanism in the pathogenesis of human anxiety disorders.

    In animals, it is well documented that the endogenous cannabinoid system has a pivotal role in the successful extinction of fear, most importantly through the cannabinoid receptor 1.

    However, no human studies have reported a translation of this preclinical evidence yet. Fear potentiation of the eyeblink startle reflex was measured to assess fear-conditioned responding, and subjective fear ratings were collected.

    Participants were genotyped for two polymorphisms located within the promoter region rs and the coding region rs of cannabinoid receptor 1. As predicted from the preclinical literature, acquisition and expression of conditioned fear did not differ between genotypes. No effects of rs genotype were observed regarding fear acquisition and extinction. These results suggest for the first time involvement of the human endocannabinoid system in fear extinction.

    Implications are that genetic variability in this system may underlie individual differences in anxiety, rendering cannabinoid receptor 1 a potential target for novel pharmacological treatments of anxiety disorders.

    Cannabinoid modulation of prefrontal-limbic activation during fear extinction learning and recall in humans. However, the effect of cannabinoids on the underlying neural circuitry of extinction memory recall in humans has not been demonstrated. This study provides the first evidence that pre-extinction administration of THC modulates prefrontal-limbic circuits during fear extinction in humans and prompts future investigation to test if cannabinoid agonists can rescue or correct the impaired behavioral and neural function during extinction recall in patients with PTSD.

    Ultimately, the cannabinoid system may serve as a promising target for innovative intervention strategies e. Endogenous cannabinoid receptor ligand induces the migration of human natural killer cells. Evidence is gradually accumulating which shows that 2-arachidonoylglycerol plays important physiological roles in several mammalian tissues and cells, yet the details remain ambiguous. In this study, we first examined the effects of 2-arachidonoylglycerol on the motility of human natural killer cells.

    We found that 2-arachidonoylglycerol induces the migration of KHYG-1 cells a natural killer leukemia cell line and human peripheral blood natural killer cells. The migration of natural killer cells induced by 2-arachidonoylglycerol was abolished by treating the cells with SR, a CB2 receptor antagonist, suggesting that the CB2 receptor is involved in the 2-arachidonoylglycerol-induced migration.

    In contrast to 2-arachidonoylglycerol, anandamide, another endogenous cannabinoid receptor ligand, did not induce the migration.

    Delta9-tetrahydrocannabinol, a major psychoactive constituent of marijuana, also failed to induce the migration; instead, the addition of delta9-tetrahydrocannabinol together with 2-arachidonoylglycerol abolished the migration induced by 2-arachidonoylglycerol. It is conceivable that the endogenous ligand for the cannabinoid receptor, that is, 2-arachidonoylglycerol, affects natural killer cell functions such as migration, thereby contributing to the host-defense mechanism against infectious viruses and tumor cells.

    Toluene Experimental Exposures in Humans: Bushnell2 and William K. Boyes2 Human subjects will be exposed to and ppm toluene for one hour in the Human St We show that a fully functional endocannabinoid system is present in primary human melanocytes normal human epidermal melanocyte cells , including anandamide AEA , 2-arachidonoylglycerol, the respective target receptors CB1, CB2, and TRPV1 , and their metabolic enzymes.

    Silencing of tyrosinase or microphthalmia-associated transcription factor further demonstrated the involvement of these proteins in AEA-induced melanogenesis. Rationale Recently, products containing synthetic cannabinoids , collectively referred to as Spice, are increasingly being used recreationally.

    Objectives The availability, acute subjective effects—including self-reports posted on Erowid—laboratory detection, addictive potential, and regulatory challenges of the Spice phenomenon are reviewed. Results Spice is sold under the guise of potpourri or incense. Unlike THC, the synthetic cannabinoids present in Spice are high-potency, high-efficacy, cannabinoid -receptor full agonists.

    Since standard urine toxicology does not test for the synthetic cannabinoids in Spice, it is often used by those who want to avoid detection of drug use. These compounds have not yet been subjected to rigorous testing in humans. Acute psychoactive effects include changes in mood, anxiety, perception, thinking, memory, and attention.

    Adverse effects include anxiety, agitation, panic, dysphoria, psychosis, and bizarre behavior. Psychosis outcomes associated with Spice provide additional data linking cannabinoids and psychosis. Adverse events necessitating intervention by Poison Control Centers, law enforcement, emergency responders, and hospitals are increasing.

    Despite statutes prohibiting the manufacture, distribution, and sale of Spice products, manufacturers are replacing banned compounds with newer synthetic cannabinoids that are not banned. Conclusions There is an urgent need for better research on the effects of synthetic cannabinoids to help clinicians manage adverse events and to better understand cannabinoid pharmacology in humans.

    The reported psychosis outcomes associated with synthetic cannabinoids contribute to the ongoing debate on the association between cannabinoids and psychosis. Finally, drug-detection tests for synthetic cannabinoids need to become clinically available. Background Cannabis is the most commonly abused drug of abuse and is commonly quantified during urine drug testing. We conducted a controlled drug administration studies investigating efficacy of urinary cannabinoid glucuronide metabolites for documenting recency of cannabis intake and for determining stability of urinary cannabinoids.

    Analytes were monitored by positive and negative mode electrospray ionization and multiple reaction monitoring mass spectrometry. Results Linear ranges were 0. Conclusion This method simultaneously quantifies urinary cannabinoids and phase II glucuronide metabolites, and enables evaluation of urinary cannabinoid glucuronides for documenting recency of cannabis intake and cannabinoid stability.

    The assay is applicable for routine urine cannabinoid testing. Screening for the synthetic cannabinoid JWH and its major metabolites in human doping controls. Referred to as 'spice', several new drugs, advertised as herbal blends, have appeared on the market in the last few years, in which the synthetic cannabinoids JWH and a C 8 homologue of CP 47, were identified as major active ingredients.

    Due to their reported cannabis-like effects, many European countries have banned these substances. The World Anti-Doping Agency has also explicitly prohibited synthetic cannabinoids in elite sport in-competition.

    Since urine specimens have been the preferred doping control samples, the elucidation of the metabolic pathways of these substances is of particular importance to implement them in sports drug testing programmes.

    In a recent report, an in vitro phase-I metabolism study of JWH was presented yielding mainly hydroxylated and N-dealkylated metabolites. The majority of the phase-I metabolites observed in earlier in vitro studies of JWH were detected in this urine specimen and furthermore most of their respective monoglucuronides. The method was applied to approximately urine doping control samples yielding two JWH findings and demonstrated its capability for a sensitive and selective identification of JWH and its metabolites in human urine.

    Cannabinoids impair the formation of cholesteryl ester in cultured human cells. The ability of cultured human fibroblasts to form cholesteryl esters from 14C-oleate is impaired by delta'-tetrahydrocannabinol, cannabidiol, and cannabinol, a group of natural products isolated from Cannabis sativa. Cells treated with these compounds at doses of from 1 to 30 microM showed no impairment of protein synthesis, triglyceride or phospholipid formation, or ability to metabolize I-low density lipoproteins.

    An inhibition of cholesterol esterification was seen in human aortic medial cells. Based on these data, we conclude that the cannabinoids "compartmentalize" cholesterol and, thus, make is unavailable for regulating cellular cholesterol metabolism. This may occur as a result of enhanced sterol efflux.

    Virodhamine relaxes the human pulmonary artery through the endothelial cannabinoid receptor and indirectly through a COX product. The endocannabinoid virodhamine is a partial agonist at the cannabinoid CB1 receptor and a full agonist at the CB2 receptor, and relaxes rat mesenteric arteries through endothelial cannabinoid receptors. Its concentration in the periphery exceeds that of the endocannabinoid anandamide.

    Here, we examined the influence of virodhamine on the human pulmonary artery. Isolated human pulmonary arteries were obtained during resections for lung carcinoma. Vasorelaxant effects of virodhamine were examined on endothelium-intact vessels precontracted with 5-HT or KCl. The vasorelaxant potency of virodhamine was lower in KCl- than in 5-HT-precontracted preparations. Virodhamine relaxes the human pulmonary artery through the putative endothelial cannabinoid receptor and indirectly through a COX-derived vasorelaxant prostanoid formed from the virodhamine metabolite, arachidonic acid.

    Disposition pathways and pharmacokinetics of herbal medicines in humans. Pharmacokinetic studies have become an integral part of modern drug development, but these studies are not regulatory needs for herbal remedies. This paper updates our current knowledge on the disposition pathways and pharmacokinetic properties of commonly used herbal medicines in humans. Some herbal ingredients are substrates of P-glycoprotein P-gp which is highly expressed in the intestine, liver, brain and kidney.

    As such, the activities of these drug metabolizing enzymes and drug transporters are determining factors for the in vivo bioavailability, disposition and distribution of herbal remedies. There are increasing pharmacokinetic studies of herbal remedies, but these studies are mainly focused on a small number of herbal remedies including St John's wort, milk thistle, sculcap, curcumin, echinacea, ginseng, ginkgo, and ginger. The pharmacokinetic data of a small number of purified herbal ingredients, including anthocyanins, berberine, catechins, curcumin, lutein and quercetin, are available.

    For the majority of herbal remedies used in folk medicines, data on their disposition and biological fate in humans are lacking or in paucity. For a herbal medicine, the pharmacological effect is achieved when the bioactive agents or the metabolites reach and sustain proper levels at their sites of action.

    Both the dose levels and fates of active components in the body govern their target-site concentrations after administration of an herbal remedy.

    In this regard, a safe and optimal use of herbal medicines requires a. Background Since , scheduling legislation of synthetic cannabinoids prompted new compound emergence to circumvent legal restrictions. Absence of parent synthetic cannabinoids in urine suggests the importance of metabolite identification for detecting RCS-4 consumption in clinical and forensic investigations.

    Most metabolites were hydroxylated with or without demethylation, carboxylation and dealkylation followed by glucuronidation. One additional sulfated metabolite was also observed. O-demethylation was the most common biotransformation and generated the major metabolite. Metabolite structural information and associated high-resolution mass spectra can be employed for developing clinical and forensic laboratory RCS-4 urine screening methods. Cannabidiol inhibits human glioma cell migration through a cannabinoid receptor-independent mechanism.

    We evaluated the ability of cannabidiol CBD to impair the migration of tumor cells stimulated by conditioned medium. CBD caused concentration-dependent inhibition of the migration of U87 glioma cells, quantified in a Boyden chamber. Since these cells express both cannabinoid CB1 and CB2 receptors in the membrane, we also evaluated their engagement in the antimigratory effect of CBD.

    These results reinforce the evidence of antitumoral properties of CBD, demonstrating its ability to limit tumor invasion, although the mechanism of its pharmacological effects remains to be clarified. The aim of this study was to develop a physiologically based pharmacokinetic PB-PK model capable of describing and predicting terbinafine concentrations in plasma and tissues in rats and humans. It was assumed that all tissues except skin and testis tissues were well-stirred compartments with perfusion rate limitations.

    The uptake of terbinafine into skin and testis tissues was described by a PB-PK model which incorporates a membrane permeability rate limitation.

    The concentration-time data for terbinafine in human plasma and tissues were predicted by use of a scaled-up PB-PK model, which took oral absorption into consideration. The predictions obtained from the global PB-PK model for the concentration-time profile of terbinafine in human plasma and tissues were in close agreement with the observed concentration data for rats. The scaled-up PB-PK model provided an excellent prediction of published terbinafine concentration-time data obtained after the administration of single and multiple oral doses in humans.

    The PB-PK model developed in this study was capable of accurately predicting the plasma and tissue terbinafine concentrations in both rats and humans and provides insight into the physiological factors that determine terbinafine disposition.

    The Synthetic Cannabinoids Phenomenon. The emergence of smokable herbal products containing synthetic cannabinoids , which mimic the effects of cannabis, appears to become increasingly popular, in the new psychoactive substances landscape. In , the existence of different types of synthetic cannabinoids were reported by the European Union Early Warning System. These drugs are mainly sold online as an alternative to controlled and regulated psychoactive substances.

    They appear to have a life cycle of about years before being replaced by a next wave of products. Legislation controlling these designer drugs has been introduced in many countries with the objective to limit the spread of existing drugs and control potential new analogs. The majority of the synthetic cannabinoids are full agonists at the CB1 receptor and do not contain tobacco or cannabis.

    They are becoming increasingly popular in adolescents, students and clubbers as an abused substance. Relatively high incidence of adverse effects associated with synthetic cannabinoids use has been documented in the literature. Numerous fatalities linked with their use and abuse have been reported. In this paper, we will review the available data regarding the use and effects of synthetic cannabinoids in humans in order to highlight their impact on public health.

    To reach this objective, a literature search was performed on two representative databases Pubmed, Google Scholar , the Erowid Center website a US non-profit educational organization that provides information about psychoactive plants and chemicals , and various governmental websites.

    The terms used for the database search were: The search was limited to years to due to emerging scientific literature at. Comprehensive Characterization of the Human Cannabinoid 1 Receptor.

    The human cannabinoid 1 receptor hCB1 , a ubiquitous G protein-coupled receptor GPCR , transmits cannabinergic signals that participate in diverse patho physiological processes.

    Pharmacotherapeutic hCB1 targeting is considered a tractable approach for treating such prevalent diseases as obesity, mood disorders, and drug addiction. The hydrophobic nature of the transmembrane helices of hCB1 presents a formidable difficulty to its direct structural analysis. Comprehensive experimental characterization of functional hCB1 by mass spectrometry MS is essential to the targeting of affinity probes that can be used to define directly hCB1 binding domains using a ligand-assisted experimental approach.

    Recombinant C-terminal hexa-histidine-tagged hCB1 His6-hCB1 was expressed in cultured insect Spodoptera frugiperda cells, solubilized by a procedure devised to enhance receptor purity following metal-affinity chromatography, desalted by buffer exchange, and digested in solution with chymo -trypsin. This work should help enable future ligand-assisted structural characterization of hCB1 binding motifs at the amino-acid level using rationally designed and targeted covalent cannabinergic probes.

    Simultaneous determination of five naphthoylindole-based synthetic cannabinoids and metabolites and their deposition in human and rat hair. The continuing appearance of new synthetic cannabinoids has been a major issue in the field of forensic and clinical toxicology.

    In response to that, analytical methods for synthetic cannabinoids have been increasingly established in a variety of biological matrices. Since most of synthetic cannabinoids with structure similarity share some enzymatic metabolites, making the interpretation of analytical results and the discovery of the parent drug actually ingested very complicated, the investigation on metabolites of the first generation of synthetic cannabinoids with their relatively short side chains in chemical structure could be more important.

    Also, using a rat model, AM and its monohydroxylated metabolites were identified and then the ratios of metabolite-to-parent drug were estimated to be used as criteria on external contamination. Matrix effect and recovery were evaluated in hair matrices and no significant variations were observed. The validation results for precision and accuracy were satisfactory in both human and rat hair. More than THC metabolites, including di- and trihydroxy compounds, ketones, aldehydes, and carboxylic acids, have been identified [ 21 ][ 70 ][ 91 ].

    Less than fivefold variability in 2C9 rates of activity was observed, while much higher variability was noted for the 3A enzyme. THC-COOH and its glucuronide conjugate are the major end products of biotransformation in most species, including man [ 91 ][ 95 ].

    The phenolic OH group may be a target as well. Addition of the glucuronide group improves water solubility, facilitating excretion, but renal clearance of these polar metabolites is low due to extensive protein binding [ 72 ].

    No significant differences in metabolism between men and women have been reported [ 27 ]. After the initial distribution phase, the rate-limiting step in the metabolism of THC is its redistribution from lipid depots into blood [ 98 ]. However, later studies did not corroborate this finding [ 8 ][ 91 ].

    More than 30 metabolites of CBD were identified in urine, with hydroxylation of the 7-Me group and subsequent oxidation to the corresponding carboxylic acid as the main metabolic route, in analogy to THC [ ]. Other tissues, including brain, intestine, and lung, may contribute to the metabolism of THC, although alternate hydroxylation pathways may be more prominent [ 86 ][ - ].

    An extrahepatic metabolic site should be suspected whenever total body clearance exceeds blood flow to the liver, or when severe liver dysfunction does not affect metabolic clearance [ ]. Within the brain, higher concentrations of CYP enzymes are found in the brain stem and cerebellum [ ]. Metabolism of THC by fresh biopsies of human intestinal mucosa yielded polar hydroxylated metabolites that directly correlated with time and amount of intestinal tissue [ ].

    In a study of the metabolism of THC in the brains of mice, rats, guinea pigs, and rabbits, Watanabe et al. Hydroxylation of C 4 of the pentyl side chain produced the most common THC metabolite in the brains of these animals, similar to THC metabolites produced in the lung. These metabolites are pharmacologically active, but their relative activity is unknown.

    CBD Metabolism is similar to that of THC, with primary oxidation of C 9 to the alcohol and carboxylic acid [ 8 ][ ], as well as side-chain oxidation [ 88 ][ ]. Co-administration of CBD did not significantly affect the total clearance, volume of distribution, and terminal elimination half-lives of THC metabolites.

    Numerous acidic metabolites are found in the urine, many of which are conjugated with glucuronic acid to increase their water solubility. Another common problem with studying the pharmacokinetics of cannabinoids in humans is the need for highly sensitive procedures to measure low cannabinoid concentrations in the terminal phase of excretion, and the requirement for monitoring plasma concentrations over an extended period to adequately determine cannabinoid half-lives.

    The slow release of THC from lipid-storage compartments and significant enterohepatic circulation contribute to a long terminal half-life of THC in plasma, reported to be greater than 4. Isotopically labeled THC and sensitive analytical procedures were used to obtain this drug half-life. No significant pharmacokinetic differences between chronic and occasional users have been substantiated [ ].

    An average of This represents an average of only 0. Prior to harvesting, cannabis plant material contains little active THC. When smoked, THC carboxylic acids spontaneously decarboxylate to produce THC, with nearly complete conversion upon heating. Pyrolysis of THC during smoking destroys additional drug. Drug availability is further reduced by loss of drug in the side-stream smoke and drug remaining in the unsmoked cigarette butt.

    These factors contribute to high variability in drug delivery by the smoked route. It is estimated that the systemic availability of smoked THC is ca.

    THC Bioavailability is reduced due to the combined effect of these factors; the actual available dose is much lower than the amount of THC and THC precursor present in the cigarette. Another factor affecting the low amount of recovered dose is measurement of a single metabolite.

    Following controlled oral administration of THC in dronabinol or hemp oil, urinary cannabinoid excretion was characterized in 4, urine specimens [ ][ ]. THC Doses of 0. The two high doses 7. The availability of cannabinoid-containing foodstuffs, cannabinoid-based therapeutics, and continued abuse of oral cannabis require scientific data for the accurate interpretation of cannabinoid tests. These data demonstrate that it is possible, but unlikely, for a urine specimen to test positive at the federally mandated cannabinoid cutoffs, following manufacturer's dosing recommendations for the ingestion of hemp oils of low THC concentration.

    An average of only 2. Specimen preparation for cannabinoid testing frequently includes a hydrolysis step to free cannabinoids from their glucuronide conjugates.

    Alkaline hydrolysis appears to efficiently hydrolyze the ester glucuronide linkage. Mean THC concentrations in urine specimens from seven subjects, collected after each had smoked a single marijuana cigarette 3. Using a modified analytical method with E.

    We found that OH-THC may be excreted in the urine of chronic cannabis users for a much longer period of time, beyond the period of pharmacodynamic effects and performance impairment. Compared to other drugs of abuse, analysis of cannabinoids presents some difficult challenges. Complex specimen matrices, i. Care must be taken to avoid low recoveries of cannabinoids due to their high affinity to glass and plastic containers, and to alternate matrix-collection devices [ - ].

    Whole-blood cannabinoid concentrations are approximately one-half the concentrations found in plasma specimens, due to the low partition coefficient of drug into erythrocytes [ 96 ][ ][ ].

    THC Detection times in plasma of 3. In the latter study, the terminal half-life of THC in plasma was determined to be ca. This inactive metabolite was detected in the plasma of all subjects by 8 min after the start of smoking. The half-life of the rapid-distribution phase of THC was estimated to be 55 min over this short sampling interval.

    The relative percentages of free and conjugated cannabinoids in plasma after different routes of drug administration are unclear. Even the efficacy of alkaline- and enzymatic-hydrolysis procedures to release analytes from their conjugates is not fully understood [ 24 ][ 77 ][ 93 ][ ][ ][ ][ - ].

    In general, the concentrations of conjugate are believed to be lower in plasma, following intravenous or smoked administration, but may be of much greater magnitude after oral intake. There is no indication that the glucuronide conjugates are active, although supporting data are lacking. Peak concentrations and time-to-peak concentrations varied sometimes considerably between subjects. Most THC plasma data have been collected following acute exposure; less is known of plasma THC concentrations in frequent users.

    No difference in terminal half-life in frequent or infrequent users was observed. There continues to be controversy in the interpretation of cannabinoid results from blood analysis, some general concepts having wide support. It is well-established that plasma THC concentrations begin to decline prior to the time of peak effects, although it has been shown that THC effects appear rapidly after initiation of smoking [ 15 ].

    Individual drug concentrations and ratios of cannabinoid metabolite to parent drug concentration have been suggested as potentially useful indicators of recent drug use [ 24 ][ ]. This is in agreement with results reported by Mason and McBay [ 96 ], and those by Huestis et al. Measurement of cannabinoid analytes with short time courses of detection e. This correlates well with the suggested concentration of plasma THC, due to the fact that THC in hemolyzed blood is approximately one-half the concentration of plasma THC [ ].

    Accurate prediction of the time of cannabis exposure would provide valuable information in establishing the role of cannabis as a contributing factor to events under investigation. Two mathematical models for the prediction of time of cannabis use from the analysis of a single plasma specimen for cannabinoids were developed [ ].

    More recently, the validation of these predictive models was extended to include estimation of time of use after multiple doses of THC and at low THC concentrations 0.

    Some 38 cannabis users each smoked a cigarette containing 2. The predicted times of cannabis smoking, based on each model, were then compared to the actual smoking times. The most accurate approach applied a combination of models I and II. All time estimates were correct for 77 plasma specimens, with THC concentrations of 0. The models provide an objective, validated method for assessing the contribution of cannabis to accidents or clinical symptoms.

    These models also appeared to be valuable when applied to the small amount of data from published studies of oral ingestion available at the time.

    Additional studies were performed to determine if the predictive models could estimate last usage after multiple oral doses, a route of administration more popular with the advent of cannabis therapies. Each of twelve subjects in one group received a single oral dose of dronabinol 10 mg of synthetic THC. In another protocol, six subjects received four different oral daily doses, divided into thirds, and administered with meals for five consecutive days.

    There was a d washout period between each dosing regimen. The daily doses were 0. The actual times between ingestion of THC and blood collection spanned 0. These results provide further evidence of the usefulness of the predictive models in estimating the time of last oral THC ingestion following single or multiple doses.

    Detection of cannabinoids in urine is indicative of prior cannabis exposure, but the long excretion half-life of THC-COOH in the body, especially in chronic cannabis users, makes it difficult to predict the timing of past drug use. This individual had used cannabis heavily for more than ten years.

    However, a naive user's urine may be found negative by immunoassay after only a few hours following smoking of a single cannabis cigarette [ ]. Assay cutoff concentrations and the sensitivity and specificity of the immunoassay affect drug-detection times. A positive urine test for cannabinoids indicates only that drug exposure has occurred. The result does not provide information on the route of administration, the amount of drug exposure, when drug exposure occurred, or the degree of impairment.

    THC-COOH concentration in the first specimen after smoking is indicative of how rapidly the metabolite can appear in urine. Thus, THC-COOH concentrations in the first urine specimen are dependent upon the relative potency of the cigarette, the elapsed time following drug administration, smoking efficiency, and individual differences in drug metabolism and excretion. The mean times of peak urine concentration were 7.

    Although peak concentrations appeared to be dose-related, there was a twelvefold variation between individuals. Drug detection time, or the duration of time after drug administration in which the urine of an individual tests positive for cannabinoids, is an important factor in the interpretation of urine drug results.

    Detection time is dependent on pharmacological factors e. Mean detection times in urine following smoking vary considerably between subjects, even in controlled smoking studies, where cannabis dosing is standardized and smoking is computer-paced.

    During the terminal elimination phase, consecutive urine specimens may fluctuate between positive and negative, as THC-COOH concentrations approach the cutoff concentration. It may be important in drug-treatment settings or in clinical trials to differentiate between new drug use and residual excretion of previously used cannabinoids. After smoking a cigarette containing 1. This had the effect of producing much longer detection times for the last positive specimen.

    Normalization of cannabinoid concentration to urine creatinine concentration aids in the differentiation of new from prior cannabis use, and reduces the variability of drug measurement due to urine dilution. Due to the long half-life of drug in the body, especially in chronic cannabis users, toxicologists and practitioners are frequently asked to determine if a positive urine test represents a new episode of drug use or represents continued excretion of residual drug.

    Random urine specimens contain varying amounts of creatinine, depending on the degree of concentration of the urine. Hawks first suggested creatinine normalization of urine test results to account for variations in urine volume in the bladder [ ].

    Whereas urine volume is highly variable due to changes in liquid, salt, and protein intake, exercise, and age, creatinine excretion is much more stable. If the increase is greater than or equal to the threshold selected, then new use is predicted. This approach has received wide attention for potential use in treatment and employee-assistance programs, but there was limited evaluation of the usefulness of this ratio under controlled dosing conditions.

    Huestis and Cone conducted a controlled clinical study of the excretion profile of creatinine and cannabinoid metabolites in a group of six cannabis users, who smoked two different doses of cannabis, separated by weekly intervals [ ]. As seen in Fig. Being able to differentiate new cannabis use from residual THC-COOH excretion in urine would be highly useful for drug treatment, criminal justice, and employee assistance drug testing programs. The ratio times of the creatinine normalized later specimen divided by the creatinine normalized earlier specimen were evaluated for determining the best ratio to predict new cannabis use.

    The most accurate ratio To further substantiate the validity of the derived ROC curve, urine-cannabinoid-metabolite and creatinine data from another controlled clinical trial that specifically addressed water dilution as a means of specimen adulteration were evaluated [ ].

    Sensitivity, specificity, accuracy, and false positives and negatives were These data indicate that selection of a threshold to evaluate sequential creatinine-normalized urine drug concentrations can improve the ability to distinguish residual excretion from new drug usage. Cannabinoids were detectable for 93 d after cessation of smoking, with a decreasing ratio of cannabinoids to creatinine over time. An excretion half-life of 32 d was determined.

    When cannabinoid concentrations had not been normalized to creatinine concentrations, a number of false positive indications of new drug use would have occurred. Within this range, cannabinoid excretion is more variable, most likely based on the slow and variable release of stored THC from fat tissue.

    The factors governing release of THC stores are not known. Additional research is being performed to attempt to determine appropriate ratio cutoffs for reliably predicting new drug use in heavy, chronic users. Oral fluid also is a suitable specimen for monitoring cannabinoid exposure, and is being evaluated for driving under the influence of drugs, drug treatment, workplace drug testing, and for clinical trials [ - ].

    The oral mucosa is exposed to high concentrations of THC during smoking, and serves as the source of THC found in oral fluid. Only minor amounts of drug and metabolites diffuse from the plasma into oral fluid [ ].

    Following intravenous administration of radiolabeled THC, no radioactivity could be demonstrated in oral fluid [ ]. Oral fluid collected with the Salivette collection device was positive for THC in 14 of these 22 participants. Several hours after smoking, the oral mucosa serves as a depot for release of THC into the oral fluid. In addition, as detection limits continue to decrease with the development of new analytical instrumentation, it may be possible to measure low concentrations of THC-COOH in oral fluid.

    Detection times of cannabinoids in oral fluid are shorter than in urine, and more indicative of recent cannabis use [ ][ ]. Oral-fluid THC concentrations temporally correlate with plasma cannabinoid concentrations and behavioral and physiological effects, but wide intra- and inter-individual variation precludes the use of oral-fluid concentrations as indicators of drug impairment [ ][ ]. THC may be detected at low concentrations by radioimmunoassay for up to 24 h after use.

    After these times, occasional positive oral-fluid results were interspersed with negative tests for up to 34 h. They suggested that the ease and non-invasiveness of sample collection made oral fluid a useful alternative matrix for detection of recent cannabis use.

    Oral-fluid samples also are being evaluated in the European Union's Roadside Testing Assessment ROSITA project to reduce the number of individuals driving under the influence of drugs and to improve road safety. The ease and non-invasiveness of oral-fluid collection, reduced hazards in specimen handling and testing, and shorter detection window are attractive attributes to the use of this specimen for identifying the presence of potentially performance-impairing drugs.

    They determined that, with a limit of quantification of 0. As mentioned above, oral-fluid specimens tested positive for up to 34 h. There is considerable debate over establishing per se laws based on blood THC concentrations.

    As medical and recreational cannabis legalization expand 18 , the debate over appropriate per se cutoffs intensifies. Fatal motor vehicle crashes with cannabis-positive drivers also increased in medical marijuana states, whereas no significant change was observed in 34 states without medical marijuana We recently evaluated effects of cannabis, with and without low-dose alcohol, on driving performance according to blood THC concentration The results documented lateral control decrements at 8.

    However, these THC concentrations were present while driving, 0. The purpose of the present analysis was to evaluate how drivers' THC concentrations decreased postinhalation before and after impaired driving, covering the typical interval between a driving incident and blood collection in the forensic setting.

    Healthy volunteers provided written informed consent for this study that was approved by the University of Iowa Institutional Review Board. At each session, participants drove for approximately 45 min between 0. In this article, postdrive refers to time after the simulated drive. BrAC measurement times were concurrent with blood collection through 3. Driving performance SD of lateral position, lane weave was previously evaluated according to blood THC concentrations during driving, modeled by individualized fitted power curves for participants' blood THC concentrations during driving, from predrive 0.

    BrAC concentrations during driving were calculated by linear curves from measurements at the same time points. Drives were subdivided into 4 segments urban, interstate, rural, rural straightway , with approximate median postdose times 0.

    Percent decreases were individually calculated within each session, and median range calculated percent decreases are presented. For reference when considering percentages, median range concentrations at starting time points also are presented in tables, since it must be considered that minor changes would result in substantial percentages if initial concentrations were low e.

    Sessions were categorized according to whether participants received active or placebo cannabis, and whether participants had residual blood THC from previous self-administration at baseline. Categories were not assigned by 2. Blood THC percent decreases relative to previous time points were compared for differences with and without alcohol by Wilcoxon matched-pairs tests, with the conservative Bonferroni correction accounting for multiple comparisons. THC concentrations in each quartile are provided above each graph.

    The box plot for each time point before and after driving in each quartile was calculated from the same participants' THC concentrations. To facilitate comparison with alcohol-positive sessions, the same concentration ranges for each quartile were established. In addition, Supplemental Figs. Box plots at each time were calculated in the same manner as during-driving box plots.

    Nineteen healthy adults 13 men and 6 women, ages 21—37 years completed the study. One individual was excluded from driving performance evaluation because of nonnormal driving behavior irrespective of dose 20 ; she also was excluded from this blood concentration analysis to ensure that reported decreases matched the driving study population.

    Self-reported demographic characteristics and recent cannabis and alcohol consumption for 19 healthy adult occasional cannabis smokers. Observed THC maximum concentration C max occurred 0. Median range C max values without and with alcohol were For placebo cannabis sessions where residual THC was observed, 0. This was likely due to his accessing active cannabis during this session, despite being under observation throughout his stay A dosing error is unlikely, on the basis of careful record review.

    Concentrations measured after driving 1. Percent decreases are presented in Tables 2 through 5 and online Supplemental Tables 1—2. No significant differences with vs without alcohol were observed. In the first 0.

    Active cannabis blood THC concentrations decreased by approximately half [ Gray shading indicates driving time; concentrations within this region were individually modeled. Dotted pattern represents likely blood collection time 1. Blood THC concentrations and percent blood THC decreases from specific time points in 18 participants' active cannabis sessions without alcohol, arranged into categories based on presence or absence of residual THC before dosing.

    Percent blood THC decreases from specific time points in 18 participants' active cannabis sessions with alcohol, arranged into categories based on presence or absence of residual THC before dosing. Concentration—time profiles and concentration decrease patterns were similar between active cannabis sessions where participants had residual THC before dosing and those without residual THC Tables 4 and 5.

    Quartiles were established by median during-drive concentrations Fig. These figures illustrate THC concentration decreases from specific, known ranges during or around driving, at later time points within the same sessions. The highest quartile in Fig. Right, Same concentration ranges matched bins for alcohol-positive sessions. Even for the highest predrive see online Supplemental Fig.

    Rapidly decreasing blood THC concentrations after inhalation do not imply rapidly decreasing impairment. THC effects are directly related to brain concentrations; peak effects do not coincide with maximum blood concentrations THC's equilibration time between blood and brain produces a delay between blood C max and maximal effects Despite marked differences in THC's pharmacodynamic vs blood pharmacokinetic profiles, it is not possible to assess brain concentrations in living drivers, and blood remains the most representative available sample.

    We previously documented impaired driving performance by these participants at specific blood THC concentrations during driving However, concentrations present after driving in the same sessions—when blood would be collected after the incident—were considerably lower.

    Unlike alcohol, which displays comparatively slow and consistent zero-order elimination kinetics 30 and can be assessed in real time by breath-testing instruments 31 , blood THC concentrations decrease rapidly after inhalation, with measured concentrations in delayed collections not reflecting concentrations present during driving. This is a crucial consideration in drugged driving interpretation and policy development because, in most cases, blood THC concentrations are substantially lower than those present at the time of the incident.

    Substantial inter- and intraindividual variability in cannabis intake, metabolism, and cannabis use history and lack of zero-order pharmacokinetics preclude back-extrapolation used with alcohol concentrations For example, we found overlapping THC concentration ranges later in the time course between quartiles of participants who had nonoverlapping concentration ranges earlier after smoking. Without reliable information about time of last intake, cannabis history, administration route, and individual metabolism, it is impossible to determine precisely how much or how rapidly concentrations decreased before collection.

    We detected SD of lateral position impairment comparable to 0. If participants' blood collection did not occur until 1.

    CYP3A4 Genetics – Importance For THC & CBD Metabolism

    18 Fourthly, systemic THC bioavailability is subjected to "smoking .. Metabolism of the cannabinoids depends mainly on their route of. The following review of literature regarding the pharmacology of marijuana is intended to demonstrate its mental and physical pharmacological effects. absorption and extensive first-pass metabolism, the bioavailability of In a previous study, the pharmacokinetics of THC were determined after pulmonary ( inh) delivery of an aqueous aerosol nebulized by a pressure-driven.

    2. Pharmacokinetics of Cannabinoids


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