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Metabolism by Driven Pharmacokinetics Cannabinoid Are



  • Metabolism by Driven Pharmacokinetics Cannabinoid Are
  • CYP3A4 Genetics – Importance For THC & CBD Metabolism
  • 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.

    Metabolism by Driven Pharmacokinetics Cannabinoid Are

    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 ]. Is there a plant based alternative that would work as well? Piperine supposedly suppresses the CYP enzymes as well. And inhibiting CYP3A4 is not for everyone since this could cause interactions with other drugs as well.

    But yes, ketoconazole will boost the bioavailability and effects of THC. Piperine probably has similar effects as well. I summarize them and send them straight to your inbox. No spam or other nonsense, just science! Over 3, scientific articles related to cannabis were published last year!

    Cannabinoid Pharmacokinetics Are Different For Everyone One of the major sources of variability in cannabinoid response is pharmacokinetics. For cannabinoids taken orally edibles , the activity of CYP enzymes can determine both: Strength of the effect — by controlling how much is metabolized prior to reaching your main circulation Duration of effect — by controlling the rate of clearance from the blood as it goes through your liver For cannabinoids taken by inhalation smoking, vaporizing , there is less importance of CYP activity since there is minimal metabolism by CYP enzymes in the lungs before absorption.

    Here are some guidelines for starting dose adjustments: Max Pixel] shares. Maynard 23 Jul Is the mechanism of action here analogous in the two cases…?? Prof of Pot 25 Jul 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.

    Marijuana effect and Deltatetrahydrocannabinol plasma level. Clin Pharmacol Ther ; High-potency marijuana impairs executive function and inhibitory motor control. Neuropsychopharmacology ; Evidence-based survey of the elimination rates of ethanol from blood with applications in forensic casework. Forensic Sci Int ; Medical Review Officer Update. American College of Occupational and Environmental Medicine ;

    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.

    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.

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