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for Cannabis Prediction Models 3.1.5. Estimation Exposure of



  • for Cannabis Prediction Models 3.1.5. Estimation Exposure of
  • Human Cannabinoid Pharmacokinetics
  • 1. Introduction
  • Plasma THC-COOH persisted for a longer period of time, following the two highest doses of Prediction Models for Estimation of Cannabis Exposure. cannabinoids and other chemicals present in the plant Cannabis sativa is being investigated Prediction Models for Estimation of Cannabis Exposure. THC decomposes when exposed to air, heat, or light; exposure to acid can oxidize the Prediction Models for Estimation of Cannabis Exposure.

    for Cannabis Prediction Models 3.1.5. Estimation Exposure of

    Electrospray ionization ESI in positive mode was used for multiple reaction monitoring and quantification of analytes. Major analyte specific mass spectrometer settings used during analysis are given in Table 1. Total ion chromatogram TIC of all the productions was used for quantification of the analytes.

    Other parameters used for validation were: Total ion chromatogram TIC of product ions was used for quantification. Cannabinoids from spiked human plasma were extracted by a simple protein precipitation method. After sonicating the mixture for 3 min, samples were vortexed for 10 s and subsequently centrifuged at 10, rpm for 5 min. All the extraction steps except drying were carried out at room temperature.

    The solution was transferred to a centrifuge tube and was spun again at 10, rpm for 5 min. The resulting clean supernatant was collected and injected into the chromatographic system. Method validation was carried out according to the general recommendation guidelines for bioanalytical methods by the US Food and Drug Administration FDA published in [ 16 ]. Various assay validation parameters including selectivity, sensitivity, accuracy, precision, recovery, and stability were determined.

    The cocktail solution was used to spike blank human plasma to generate calibrators and quality control QC samples. Selectivity of the assay in blank plasma was assessed visually for any presence of endogenous matrix components at the analyte specific retention times. Further, we studied the selectivity in plasma from seven different donors at LLOQ. The sensitivity of the method was the lowest analyte concentration measured with acceptable accuracy and precision LLOQ.

    An eight-point calibration curve with concentrations ranging from 1. Inter-run precision and accuracy of the assay were calculated from six different calibration curves. Chromatographic conditions were optimized to separate the elution region of phospholipids and analytes of interest.

    A post-column divert valve was used to guide unwanted portion of chromatographic runs, mainly containing phospholipids. Matrix effect was studied using post-column infusion method as described elsewhere [ 17 , 19 ]. Drug-free plasma was spiked in triplicates at HQC in plasma isolated using three separate anticoagulants i. The proposed method was developed in collaboration with co-authors at Brown University for estimation of analytes in human plasma from self-reported marijuana users.

    In this manuscript, we report the application of the method by estimating cannabinoids in plasma from six subjects. We evaluated several mobile phases and C18 analytical columns and found that the current approach provided adequate separation of the two major constituents THC and CBD of marijuana.

    THC eluted at 2. The mean deviation in RT over the six validation runs for all the analytes was less than 0. The precursor and product ions used in the assay Table 1 were found to be in agreement with the fragmentation proposed previously [ 20 ]. No interference was visually observed at the retention time of analytes in blank plasma extracted from seven different donors. An LLOQ of 1. Chromatograms for blank plasma green and spiked plasma sample at the lower limit of quantification red.

    An eight-point calibration curve Fig. The accuracy of the assay for different analytes was between The extraction recovery of the method for all analytes in the assay ranged from Most of the phospholipids eluted after the analytes.

    However we noticed some overlap for THC Fig. Elution of analytes and major plasma phospholipids in chromatography. The region of signal suppression due to the elution of endogenous matrix components observed by injection of extracted blank plasma and continuous infusion of analytes post-column.

    Although the method was validated with blank plasma collected with potassium-EDTA, as part of method adaptability, the effect of various anticoagulants on the extraction of analytes spiked at HQC was studied. The results from sodium heparin were found to be closer to potassium-EDTA than sodium fluoride-potassium oxalate.

    The assay was successfully applied for quantification of cannabinoids in plasma from six subjects Table 7. C hromatogram of cannabinoids that was quantified in plasma from one self-reported cannabis user is shown in Fig. Representative chromatogram of cannabinoids quantified in plasma from one self-reported cannabis user study volunteer. Concentration of cannabinoids estimated in human plasma from six self-reported cannabis users. Previously reported methods for quantification of cannabinoids in human plasma and serum rely on tedious, multi-step liquid-liquid extraction or solid-phase extraction techniques.

    Moreover, LLOQ of the current assay for all analytes 1. Although the extraction solvent diluted the analytes, we dried the samples after extraction and reconstituted to achieve a lower quantification range suitable for clinical analysis.

    This approach allowed us to analyze all the analytes in positive ion operation mode. Anticoagulant used for collection of plasma could influence the analysis and stability of analytes. Scheidweiler and colleagues recently reported a long-term stability between 6 and 9 months study for cannabinoids depending on the anticoagulant and storage conditions [ 27 ].

    Phospholipids are responsible for endogenous matrix effects and ion suppression in the analysis of compounds in human plasma and serum [ 18 ]. Ion suppression in ACN protein precipitation methods is a common drawback of such assays [ 19 ].

    However, where good separation between analytes and region of suppression is not achieved, an appropriate internal standard should be included in the assay to account for the suppression of co-eluting analyte.

    Additionally, we confirmed that acidic extraction conditions did not interfere with the assay by conversion of CBD into THC. A previous study reported the unsuitability of derivatizing reagents Trifluoroacetic anhydride, TFAA for quantification of cannabinoids due to the conversion of CBD to THC under acidic conditions [ 28 ].

    The suitability of our method was investigated by extraction of plasma spiked with CBD 0, The use of cannabis with ethanol is usually reported among fatal motor vehicle accidents, and the detrimental effects appear to be dose-dependent [ 29 ].

    Also, estimating the time of last use of cannabis in user is complicated due to polymorphic differences and different metabolism in frequent versus non-frequent users. Higher plasma and urine concentration of THC metabolites were reported in frequent marijuana users without any change in other pharmacokinetic parameters namely, area under the curve, the volume of distribution and elimination half-lives [ 31 ]. The application of the proposed method for analysis of clinical samples was examined by quantification of cannabinoids in human plasma.

    We could detect THC in three subjects who had self-reported use of marijuana. Since the blood collection was not part of a controlled study, the authors have no information on the time of last use or the concentration of THC present in marijuana.

    Overall, a simple protein precipitation method for extraction of analytes of interest presents a fast and economical tool for quantitative analysis of cannabinoids. The method was applied successfully for quantification of all the analytes relevant to study THC exposure in plasma and can be easily adapted for similar pharmacokinetic studies in human.

    This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form.

    Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Europe PMC requires Javascript to function effectively. The assay was validated according to guidelines set forth by Food and Drug Administration of the United States.

    The snippet could not be located in the article text. This may be because the snippet appears in a figure legend, contains special characters or spans different sections of the article. Author manuscript; available in PMC Mar Rohitash Jamwal , a Ariel R.

    Abstract Cannabis is used widely in the United States, both recreationally and for medical purposes. Introduction Cannabis sativa L. Open in a separate window. Materials and methods 2. Mass spectrometry conditions Electrospray ionization ESI in positive mode was used for multiple reaction monitoring and quantification of analytes.

    There was no correlation between blood and brain concentrations; brain levels were always higher than blood levels, and in three cases measurable drug concentrations remained in the brain, when no longer detectable in the blood.

    Blood concentrations were lower than in the two-paired brains. The authors postulate that long-lasting effects of cannabis during abstinence in heavy users may be due to residual THC and OH-THC concentrations in the brain.

    Storage of THC after chronic exposure could also contribute to observed toxicities in other tissues. After single intramuscular administration of radioactive THC in rats, only 0. The authors suggest that the blood—brain and blood—testicular barriers limit storage of THC in brain and testis during acute exposure; however, during THC chronic exposure, pharmacokinetic mechanisms are insufficient to prevent accumulation of THC in tissues, with subsequent deregulation of cellular processes, including apoptosis of spermatogenic cells.

    In one of the latest investigations on THC distribution in tissues, the large-white-pig model was selected due to similarities with humans in drug biotransformation, including enzymes and isoenzymes of drug biotransformation, size, feeding patterns, digestive physiology, dietary habits, kidney structure and function, pulmonary vascular bed structure, coronary-artery distribution, propensity to obesity, respiratory rates, and tidal volume [ 75 ].

    THC Plasma pharmacokinetics was found to be similar to those in humans. At 30 min, high THC concentrations were noted in lung, kidney, liver, and heart, with comparable elimination kinetics in kidney, heart, spleen, muscle, and lung as observed in blood. The fastest THC elimination was noted in liver, where concentrations fell below measurable levels by 6 h. Mean brain concentration was approximately twice the blood concentration at 30 min, with highest levels in the cerebellum, and occipital and frontal cortex, and lowest concentrations in the medulla oblongata.

    THC Concentrations decreased in brain tissue slower than in blood. The slowest THC elimination was observed for fat tissue, where THC was still present at substantial concentrations 24 h later.

    The authors suggest that the prolonged retention of THC in brain and fat in heavy cannabis users is responsible for the prolonged detection of THC-COOH in urine and cannabis-related flashbacks. The author of this review hypothesizes that this residual THC may also contribute to cognitive deficits noted early during abstinence in chronic cannabis users.

    THC accumulation in the lung occurs because of high exposure from cannabis smoke, extensive perfusion of the lung, and high uptake of basic compounds in lung tissue. Lung tissue is readily available during postmortem analysis, and would be a good matrix for investigation of cannabis exposure.

    Other possible explanations include lower plasma-protein binding of OH-THC or enhanced crossing of the blood—brain barrier by the hydroxylated metabolite. The distribution volume V d of THC is large, ca. More recently, with the benefit of advanced analytical techniques, the steady state V d value of THC was estimated to be 3.

    THC-COOH was found to be far less lipophilic than the parent drug, whose partition coefficient P value at neutral pH has been measured at 6, or higher , and more lipophilic than the glucuronide [ 78 ].

    The fraction of THC glucuronide present in blood after different routes of administration has not been adequately resolved, but, recently, the partition coefficient of this compound indicated an unexpectedly high lipophilicity, ca.

    THC rapidly crosses the placenta, although concentrations were lower in canine and ovine fetal blood and tissues than in maternal plasma and tissues [ 79 ]. Blackard and Tennes reported that THC in cord blood was three to six times less than in maternal blood [ 82 ]. Transfer of THC to the fetus was greater in early pregnancy. THC also concentrates into breast milk from maternal plasma due to its high lipophilicity [ 83 ][ 84 ].

    THC Concentration in breast milk was 8. They also documented that THC can be metabolized in the brain. Conjugation with glucuronic acid is a common Phase-II reaction. Side-chain hydroxylation was common in all three species. THC Concentrations accumulated in the liver, lung, heart, and spleen. Hydroxylation of THC at C 9 by the hepatic CYP enzyme system leads to production of the equipotent metabolite OH-THC [ 89 ][ 90 ], originally thought by early investigators to be the true psychoactive analyte [ 64 ].

    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. Positive oral-fluid cannabinoid tests were not obtained more than 2 h after last use, suggesting that much lower cutoff concentrations were needed to improve sensitivity. Detection of cannabinoids in oral fluid is a rapidly developing field; however, there are many scientific issues to resolve.

    One of the most important is the degree of absorption of the drug to oral-fluid collection devices. Recently, there has been renewed interest in oral-fluid drug testing for programs associated with drug treatment, workplace, and driving under the influence of drugs. Small and inconsistent specimen volume collection, poor extraction of cannabinoids from the collection device, low analyte concentrations for cannabinoids, and the potential for external contamination from environmental smoke are limitations to this monitoring method.

    Recently, independent evaluations of the extraction of cannabinoids from the collection device [ - ] and measurement of oral-fluid THC-COOH in concentrations as low as picograms per milliliter appear to adequately address these potential problems. The extraction efficiency of the buffer was reported to be between Specimens collected almost immediately after smoking cannabis, i.

    Some 95 specimens This limitation has curtailed the use of oral-fluid testing to monitor cannabis use. First, oral-fluid collection devices were contaminated when opened within the smoke-filled car.

    When the specimens were collected outside of the car, immediately following smoking, specimens from passive smokers were negative. Environmental cannabis smoke can contaminate collection devices, unless specimens are collected outside the area of smoke contamination.

    To date, there are no published data on the excretion of cannabinoids in sweat following controlled THC administration, although our laboratory at NIH is conducting such research. Sweat testing is being applied to monitor cannabis use in drug treatment, criminal justice, workplace drug testing, and clinical studies [ ][ ]. In , Balabanova and Schneider used radioimmunoassay to detect cannabinoids in apocrine sweat [ ].

    Generally, the patch is worn for 7 d, and then exchanged for a new patch once each week during visits to the treatment clinic or parole officer. Theoretically, this permits constant monitoring of drug use throughout the week, extending the window of drug detection and improving test sensitivity.

    As with oral-fluid testing, this is a developing analytical technique, with much to be learned about the pharmacokinetics of cannabinoid excretion in sweat, potential re-absorption of THC by the skin, possible degradation of THC on the patch, and adsorption of THC onto the patch-collection device. Understanding the pharmacokinetics of THC excretion also is important for the interpretation of hair cannabinoid tests, as sweat has been shown to contribute to the amount of drug found in hair see below.

    Several investigators have evaluated the sensitivity and specificity of different screening assays for detecting cannabinoids in sweat [ ][ ]. The same investigators also evaluated forehead swipes with cosmetic pads for monitoring cannabinoids in sweat from individuals suspected of driving under the influence of drugs [ ].

    There are multiple mechanisms for the incorporation of cannabinoids in hair. THC and its metabolites may be incorporated into the hair bulb that is surrounded by capillaries. Drug may also diffuse into hair from sebum secreted onto the hair shaft, and from sweat excreted onto the skin surface. Drug may also be incorporated into hair from the environment. Cannabis is primarily smoked, providing an opportunity for environmental contamination of hair with THC in cannabis smoke.

    Basic drugs such as cocaine and methamphetamine concentrate in hair due to ionic bonding to melanin, the pigment in hair that determines hair color. The more neutral and lipophilic THC is not strongly bound to melanin, resulting in much lower concentrations of THC in hair as compared to other drugs of abuse.

    An advantage of measuring THC-COOH in hair is that this compound is not present in cannabis smoke, avoiding the issue of passive exposure from the environment. Analysis of cannabinoids in hair is challenging due to the high analytical sensitivity required. It is difficult to conduct controlled cannabinoid-administration studies on the disposition of cannabinoids in hair because of the inability to differentiate administered drug from previously self-administered cannabis.

    If isotopically labeled drug were administered, it would be possible to identify newly administered drug in hair. There are advantages to monitoring drug use with hair testing, including a wide window of drug detection, a less invasive specimen-collection procedure, and the ability to collect a second specimen at a later time.

    However, one of the weakest aspects of testing for cannabinoids in hair is the low sensitivity of drug detection in this alternate matrix. In the only controlled cannabinoid dosing study published to date, Huestis et al.

    Human Cannabinoid Pharmacokinetics

    Effect of different anticoagulants. Although the method was validated with . Also, estimating the time of last use of cannabis in user is complicated .. Models for the prediction of time of marijuana exposure from plasma. Natural cannabis products and single cannabinoids are usually inhaled or taken orally; the rectal route, sublingual administration, Sublingual Administration Arzneim-. trometry for the determination of ∆9- tetrahydrocannabinol and models for the prediction of time of marijuana exposure from. PDF | Cannabis is used widely in the United States, both recreationally and for medical purposes Predictive model accuracy in estimating last.

    1. Introduction



    Effect of different anticoagulants. Although the method was validated with . Also, estimating the time of last use of cannabis in user is complicated .. Models for the prediction of time of marijuana exposure from plasma.


    Natural cannabis products and single cannabinoids are usually inhaled or taken orally; the rectal route, sublingual administration, Sublingual Administration Arzneim-. trometry for the determination of ∆9- tetrahydrocannabinol and models for the prediction of time of marijuana exposure from.


    PDF | Cannabis is used widely in the United States, both recreationally and for medical purposes Predictive model accuracy in estimating last.


    Summary. Figure Venue of drug exposure for patients testing positive to THC (n = ). . pre-study estimates were made, and the use of benzodiazepines among Illicit Drug Users is .. Rates of psycho-stimulant detection were greater than the pre-study prediction (22% of all .. Models similar to D2EWS are.


    Plasma insulin determination using radioimmunoassay (RIA). . Effect of hours of C. sativa exposure ( ng/mL THC), with and without vivo diet- induced obese rat model and an in vitro isolated rat Based on the experimental data (figure ), a validated predictive qPCR on GOI.


    case in more detail, the latter being the generic model for THC .. Italy .. Estimation of the dietary exposure (chronic and acute dietary the predictive values (and relative economy) of studying drug effects in animals.

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