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by Driven Metabolism Cannabinoid Are Pharmacokinetics



  • by Driven Metabolism Cannabinoid Are Pharmacokinetics
  • Human Cannabinoid Pharmacokinetics
  • 1. Introduction
  • 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 Driven Metabolism Cannabinoid Are Pharmacokinetics

    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. Additionally, in most forensic cases, time since last intake relative to crash or traffic stop is unknown, and the 1. For this reason, we evaluated percent decreases from concentrations at other time points as well as 0. If time postinhalation were known, concentration decreases would be most comparable to percent decreases from 0.

    Prior frequent cannabis intake history produces the additional complication of residual THC, as we demonstrated. Because subsets of participants with and without residual THC for different sessions were not completely matched, differences in THC concentration decreases with vs without residual THC could not be directly compared.

    In forensic cases, it is not possible to know whether there was residual THC or not before acute self-administration; baseline concentrations are a crucial consideration in chronic frequent smokers. The use of more conservative decrease estimates Tables 4 and 5 determined from the sessions with residual THC would afford suspects the benefit of the doubt. Concentrations returned to individual baselines within approximately 4. Residual blood THC concentrations' fluctuation in this study's participants after placebo cannabis was consistent with gradual extended THC release after chronic frequent smoking 11 — Although evidence suggests partial tolerance to some acute cannabis psychomotor impairment effects with chronic frequent intake, not all effects show tolerance 33 — Many jurisdictions adopted zero-tolerance laws to counteract blood THC pharmacokinetics' challenges, but increasing medical and recreational cannabis legalization intensifies the debate over zero-tolerance and per se laws for frequent smokers.

    In cannabis-only fatal crash cases, blood THC detected at any concentration in drivers was significantly associated with 2.

    Apart from more stringent per se laws, other possible strategies to combat blood THC decreases in DUIC include implementation of alternative matrices testing. Dried blood spots or breath collection represent promising alternatives, due to noninvasiveness and roadside collections; however, cannabinoid concentrations are low in these matrices, and much additional research is required before either is feasible.

    Breath detection windows are currently limited to approximately 2 h postsmoking 39 , whereas impairing effects may extend beyond this period.

    Oral fluid is a promising noninvasive matrix, with roadside screening applicability and detection windows comparable to acute impairment windows if recent use markers are included In DUIC, it is crucial to consider sample collection time relative to when the incident occurred. Blood THC concentrations measured in forensic cases may be lower than common per se cutoffs despite greatly exceeding them during driving.

    Although the interval between traffic stop and blood collection—and THC concentration at the time of collection—are known, the time of cannabis intake in relation to driving is unknown. There also is individual variability around the THC concentration during driving, and the rate of decrease varies on the basis of an individual's intake frequency, metabolism, and elimination rate. In our data, THC concentration ranges hours after driving were similar across multiple quartiles despite there being no overlap in THC concentrations across quartiles during driving.

    These data provide THC concentration decreases over time for documenting decreases with delayed blood collection. Improvement in interpretation of blood THC concentrations requires blood collection as soon as possible after the incident or traffic stop due to rapid concentration decreases over time. Blood should be collected at the start of any impairment evaluation or collected roadside by trained police officers. As legalized medical and recreational cannabis access expand, residual THC and potential partial tolerance with chronic frequent intake will be relevant to more individuals, further complicating per se debates.

    An alternative is requiring documentation of impairment, or a combination of statues that includes penalties on the basis of per se or impairment. Decisions regarding DUIC legislation are driven by objective scientific data and societal priorities.

    Legislative policy is established by societies' balance of individual rights vs public safety, a balance that varies over time. Russell Pierce VariableSolutions ; and Drs. All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: Authors' Disclosures or Potential Conflicts of Interest: Upon manuscript submission, all authors completed the author disclosure form.

    Spurgin, International Association of Chiefs of Police. The funding organizations played a direct role in the design of study. Skip to main content. Hartman , Timothy L. Gorelick , Gary R. Gaffney , Marilyn A. This article has a correction. Correction - June 01, Results Nineteen healthy adults 13 men and 6 women, ages 21—37 years completed the study.

    View inline View popup. Median range positive blood THC concentrations over time 18 participants; after 0. Discussion Rapidly decreasing blood THC concentrations after inhalation do not imply rapidly decreasing impairment. Conclusion In DUIC, it is crucial to consider sample collection time relative to when the incident occurred.

    Consultant or Advisory Role: National Highway Traffic Safety Administration ; Alcohol and drugs in seriously injured drivers in six European countries. Drug Test Anal ; 5: Marijuana use and motor vehicle crashes. Epidemiol Rev ; Acute cannabis consumption and motor vehicle collision risk: BMJ ; Traffic Inj Prev ; 9: Driving under the influence of cannabis: Addiction ; Routes of administration of cannabis used for nonmedical purposes and associations with patterns of drug use.

    J Adolesc Health ; J Anal Toxicol ; Pharmacokinetics and metabolism of the plant cannabinoids, Delta9-tetrahydrocannabinol, cannabidiol and cannabinol. Handb Exp Pharmacol ; Controlled cannabis vaporizer administration: Clin Chem ; Phase I and II cannabinoid disposition in blood and plasma of occasional and frequent smokers following controlled smoked cannabis.

    Do Delta9-tetrahydrocannabinol concentrations indicate recent use in chronic cannabis users? Impact of prolonged cannabinoid excretion in chronic daily cannabis smokers' blood on per se drugged driving laws. Should per se limits be imposed for cannabis? Equating cannabinoid blood concentrations with actual driver impairment: Humboldt J Soc Relat ; Driving while stoned difficult to define, regulate in Colorado. The Denver Post ; Colorado medical marijuana users sound off on bill that would limit THC levels for drivers.

    The Huffington Post ; Analysis of Delta9-tetrahydrocannabinol driving under the influence of drugs cases in Colorado from January to February Trends in fatal motor vehicle crashes before and after marijuana commercialization in Colorado. Drug Alcohol Depend ; Cannabis effects on driving lateral control with and without alcohol.

    A prototype screening instrument for cannabis use disorder: Drug Alcohol Rev ; Assessing the feasibility of vehicle-based sensors to detect alcohol impairment. In vitro stability of free and glucuronidated cannabinoids in blood and plasma following controlled smoked cannabis. Direct quantification of cannabinoids and cannabinoid glucuronides in whole blood by liquid chromatography—tandem mass spectrometry. Anal Bioanal Chem ; Psychomotor performance, subjective and physiological effects and whole blood delta9-tetrahydrocannabinol concentrations in heavy, chronic cannabis smokers following acute smoked cannabis.

    Cannabinoid pharmacokinetics encompasses absorption after diverse routes of administration and from different drug formulations, analyte distribution throughout the body, metabolism by the liver and extra-hepatic tissues, and elimination in the feces, urine, sweat, oral fluid, and hair.

    Pharmacokinetic processes are dynamic, may change over time, and may be affected by the frequency and magnitude of drug exposure. The many contributions to our understanding of cannabinoid pharmacokinetics from the s and s are reviewed, and the findings of recent research expanding upon this knowledge are detailed.

    Cannabinoid pharmacokinetics research is challenging due to low analyte concentrations, rapid and extensive metabolism, and physico-chemical characteristics hindering the separation of drugs of interest from biological matrices and from each other.

    Drug recovery is reduced due to adsorption of compounds of interest to multiple surfaces. Much of the early cannabinoid data are based on radiolabeled cannabinoids yielding highly sensitive, but less specific, measurement of individual cannabinoid analytes.

    New extraction techniques and mass-spectrometric MS developments now permit highly sensitive and specific measurement of cannabinoids in a wide variety of biological matrices, improving our ability to characterize cannabinoid pharmacokinetics.

    Cannabis sativa contains over different chemical compounds, including over 60 cannabinoids [ 1 - 3 ]. Cannabinoid plant chemistry is far more complex than that of pure THC, and different effects may be expected due to the presence of additional cannabinoids and other chemicals.

    Eighteen different classes of chemicals, including nitrogenous compounds, amino acids, hydrocarbons, carbohydrates, terpenes, and simple and fatty acids, contribute to the known pharmacological and toxicological properties of cannabis. THC is usually present in Cannabis plant material as a mixture of monocarboxylic acids, which readily and efficiently decarboxylate upon heating.

    THC decomposes when exposed to air, heat, or light; exposure to acid can oxidize the compound to cannabinol CBN , a much less-potent cannabinoid. In addition, cannabis plants dried in the sun release variable amounts of THC through decarboxylation.

    During smoking, more than 2, compounds may be produced by pyrolysis. Route of drug administration and drug formulation determine the rate of drug absorption. Smoking, the principal route of cannabis administration, provides a rapid and efficient method of drug delivery from the lungs to the brain, contributing to its abuse potential.

    Intense pleasurable and strongly reinforcing effects may be produced due to almost immediate drug exposure to the central nervous system CNS. Slightly lower peak THC concentrations are achieved after smoking as compared to intravenous administration [ 5 ]. The number, duration, and spacing of puffs, hold time, and inhalation volume, or smoking topography, greatly influences the degree of drug exposure [ 10 - 12 ].

    Expectation of drug reward also may affect smoking dynamics. The disposition of THC and its metabolites were followed for a period of 7 d after smoking a single placebo, and cigarettes containing 1. THC concentrations were 7. THC, detected in plasma immediately after the first cigarette puff Fig. Concentrations increased rapidly, reaching mean peaks of Peak concentrations occurred at 9.

    Despite a computer-paced smoking procedure that controlled the number of puffs, length of inhalation, hold time, and time between puffs, there were large inter-subject differences in plasma THC concentrations due to differences in the depth of inhalation, as participants titrated their THC dose Fig. The mean THC concentrations were ca. Time-dependent THC concentrations for six individuals subjects B, C, and E—H following smoking of a single cannabis cigarette containing 3.

    Reprinted and adapted with permission by Journal of Analytical Toxicology, p. Similar mean maximum THC concentrations were reported in specimens collected immediately after cannabis smoking was completed. The mean peak THC concentrations were Other reported peak THC concentrations ranged between The smoking route is preferred by many cannabis users because of its rapid drug delivery and resultant fast onset of effects, but also for the ability to titrate dose to the desired degree of effect.

    In our controlled smoked-cannabis experiments described above, the individual with the lowest peak plasma concentration had the greatest cardiovascular response [ 15 ]. The average concentrations in more than 30, cannabis preparations confiscated in the U. However, cannabis-based medicine extracts and clinical-grade cannabis contain high quantities of CBD, which frequently equal the percentage of THC [ 19 ].

    There are fewer studies on the disposition of THC and its metabolites after oral administration of cannabis as compared to the smoked route. The advantages of cannabinoid smoking are offset by the harmful effects of cannabinoid smoke; hence smoking is generally not recommended for therapeutic applications. In addition, abuse of cannabis by the oral route also is common. Absorption is slower when cannabinoids are ingested, with lower, more-delayed peak THC concentrations [ 24 ][ 25 ].

    Dose, route of administration, vehicle, and physiological factors such as absorption and rates of metabolism and excretion can influence drug concentrations in circulation. Glycocholate and sesame oil improved the bioavailability of oral THC; however, there was considerable variability in peak concentrations and rates of absorption, even when the drug was administered in the same vehicle.

    Participants were dosed with either 15 mg women or 20 mg men of THC dissolved in sesame oil and contained in gelatin capsules. THC Plasma concentrations peaked ca. A percentage of the THC was radiolabeled; however, investigators were unable to differentiate labeled THC from its labeled metabolites. Thus, THC concentrations were overestimated. Possibly a more accurate assessment of oral bioavailability of THC in plasma samples was reported by Ohlsson et al.

    The peak THC concentrations ranged from 4. Potential new indications include the reduction of spasticity, analgesia, and as an agonist-replacement pharmacotherapy for cannabis dependence. Thus, the pharmacokinetics of oral THC is of great importance to the successful application of new therapeutic approaches. Interestingly, two THC peaks frequently were observed due to enterohepatic circulation. Onset is delayed, peak concentrations are lower, and duration of pharmacodynamic effects generally are extended with a delayed return to baseline, when THC is administered by the oral as compared to the smoked route [ 29 ][ 30 ].

    In addition, THC-containing foods, i. The THC content depends upon the effectiveness of cannabis-seed-cleaning and oil-filtration processes. Currently, the THC concentrations of hemp oil in the U. In a recent, controlled cannabinoid-administration study of THC-containing hemp oils and dronabinol, the pharmacokinetics and pharmacodynamics of oral THC were evaluated.

    There was a d washout phase between each of the five dosing sessions. This could be due to the formulation of dronabinol, which afforded greater protection from degradation in the stomach due to encapsulation and perhaps, improved bioavailability of THC in sesame oil, the formulation of synthetic THC or dronabinol.

    Reprinted and adapted with permission by Elsevier, p. After oral THC dosing, Nadulski et al. Due to low bioavailability of oral THC formulations, alternative routes of drug administration, including oromucosal or sublingual dosing, vaporization of product and inhalation, and rectal administration, have been developed to improve the amount of delivered cannabinoids.

    Due to the chemical complexity of cannabis plant material compared to synthetic THC, extracts of cannabis that capture the full range of cannabinoids are being explored as therapeutic medications. Cannabis has been used as medicine for thousands of years [ 34 ][ 35 ]. Clinical trials of the efficacy of these extracts are ongoing for analgesia [ 37 ][ 38 ] and spasticity, and other indications in affected patients [ 39 ].

    Several different suppository formulations were evaluated in monkeys to determine the matrix that maximizes bioavailability and reduces first-pass metabolism [ 40 ][ 41 ]; THC-hemisuccinate provided the highest bioavailability of Rectal administration of 2. The bioavailability of the rectal route was approximately twice that of the oral route due to higher absorption and lower first-pass metabolism.

    Another route of cannabinoid exposure that avoids first-pass metabolism and improves THC bioavailability is topical administration [ 43 ]. Cannabinoids are highly hydrophobic, making transport across the aqueous layer of the skin the rate-limiting step in the diffusion process [ 44 ][ 45 ]. In vitro diffusion studies may underestimate in vivo transdermal flux [ 43 ]. In vivo studies of transdermal drug delivery in guinea pigs noted the presence of significant amounts of plasma metabolites after topical application of THC [ 46 ].

    Additional research is planned with combinations of cannabinoids in EtOH to increase drug absorption. Transdermal delivery of cannabinoids is hoped to reduce negative side effects seen with inhalation dosing [ 47 ]. Transdermal delivery also bypasses first-pass metabolism of cannabinoids. These properties could improve the utility of transdermal cannabinoid medications.

    Applying a transdermal patch several hours before chemotherapy, and wearing it for several days, would be a convenient means for treating associated nausea and vomiting. Also, wearing a patch for a week to stimulate appetite could be a good alternative to twice a day oral dosing of dronabinol. The drug-abuse potential of cannabinoid transdermal patches is expected to be low because of slow delivery of THC to the brain.

    However, extraction of cannabinoids from the patch for administration by a more-rapid method has not been evaluated. Diversion of fentanyl patches by drug abusers for use in such a manner has been a significant problem. Although THC is not abused by the intravenous route, pharmacodynamic and pharmacokinetic cannabinoid research has employed this technique.

    Recently, D'Souza et al. The double-blind, randomized, and placebo-controlled study investigated the behavioral, cognitive, and endocrine effects of 0, 2. Some subjects withdrew from the study due to acute paranoia 1 , panic 1 , hypotension 2 , withdrawal of consent due to dislike of THC effects 3 , and other issues 2.

    One subject experienced a significant, acute paranoid reaction and was treated with 2 mg lorazepam. THC produced schizophrenia-like positive and negative symptoms and euphoria, and altered aspects of cognitive function. Plasma cortisol concentrations were not affected. THC produced a broad range of transient symptoms, behaviors, and cognitive deficits in healthy individuals that resembled endogenous psychoses. The investigators suggested that brain-cannabinoid-receptor function could be an important factor in the pathophysiology of psychotic disorders.

    Cannabidiol CBD is a natural, non-psychoactive [ 49 ][ 50 ] constituent of Cannabis sativa , but possesses pharmacological activity, which is explored for therapeutic applications. CBD has been reported to be neuroprotective [ 51 ], analgesic [ 37 ][ 38 ][ 52 ], sedating [ 37 ][ 38 ][ 53 ][ 54 ], anti-emetic [ 54 ], anti-spasmodic [ 55 ], and anti-inflammatory [ 56 ].

    In addition, it has been reported that CBD blocks anxiety produced by THC [ 57 ], and may be useful in the treatment of autoimmune diseases [ 53 ]. These potential therapeutic applications alone warrant investigation of CBD pharmacokinetics. Further, the controversy over whether CBD alters the pharmacokinetics of THC in a clinically significant manner needs to be resolved [ 58 ][ 59 ].

    Recently, Nadulski et al. The authors suggest that identification and quantification of CBD could be an additional proof of cannabis exposure and could improve interpretation of THC effects considering the potential ability of CBD to modify THC effects.

    When comparing sublingual administration of THC 25 mg alone vs. The only statistically significant difference was in the time of maximum THC concentration. All three analytes were detectable ca. High intra- and inter-subject variability was noted. THC Plasma concentrations decrease rapidly after the end of smoking due to rapid distribution into tissues and metabolism in the liver. THC is highly lipophilic and initially taken up by tissues that are highly perfused, such as the lung, heart, brain, and liver.

    Tracer doses of radioactive THC documented the large volume of distribution of THC and its slow elimination from body stores. In animals, after intravenous administration of labeled THC, higher levels of radioactivity were present in lung than in other tissues [ 64 ].

    Studies of the distribution of THC into brain are especially important for understanding the relationships between THC dose and behavioral effects.

    Plasma concentrations were of similar magnitude to those measured in men exposed to marihuana smoke. Kreuz and Axelrod were the first to describe the persistent and preferential retention of radiolabeled THC in neutral fat after multiple doses, in contrast to limited retention in brain [ 66 ].

    The ratio of fat to brain THC concentration was approximately With prolonged drug exposure, THC concentrates in human fat, being retained for extended periods of time [ 69 ]. In addition, these investigators found that tolerance to the behavioral effects of THC in pigeons was not due to decreased uptake of cannabinoids into the brain. Tolerance also was evaluated in humans. Pharmacokinetic changes after chronic oral THC administration could not account for observed behavioral and physiologic tolerance, suggesting rather that tolerance was due to pharmacodynamic adaptation.

    Adams and Martin studied the THC dose required to induce pharmacological effects in humans [ 73 ]. In a recent, highly interesting study, Mura et al. 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.

    Human Cannabinoid Pharmacokinetics

    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.

    1. Introduction



    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.


    To determine first-pass metabolism (Fg·Fh), drug depletion studies led to reasonably good predictions of the oral bioavailability of THC in.


    In vitro experiments demonstrated that when compared to ∆9-THC, and pharmacokinetic properties relative to Δ9-THC that may contribute to the In fact, the beneficial combination of cannabidiol with Δ9-THC led to.


    Temperature-controlled, electrically-driven vaporizers efficiently gastric fluid and an extensive first pass metabolism in gut and liver. absorption of THC released as liquid aerosol from a pressure-driven nebulizer [29].

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