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Summary sheet: Tetrahydrocannabinol Template:SubstanceBox/TetrahydrocannabinolPW
🧬 Receptor activityPH
Mechanism of actionPH
Dronabinol is a synthetic form of delta-9-tetrahydrocannabinol (Δ⁹-THC), the primary psychoactive component of cannabis (marijuana). THC demonstrates its effects through weak partial agonist activity at Cannabinoid-1 (CB1R) and Cannabinoid-2 (CB2R) receptors, which results in the well-known effects of smoking cannabis such as increased appetite, reduced pain, and changes in emotional and cognitive processes.
The availability of potent synthetic agonists for cannabinoid receptors has facilitated our understanding of cannabinoid actions on synaptic transmission in the central nervous system. Moreover, the ability of these compounds to inhibit neurotransmitter release at many central synapses is thought to underlie most of the behavioral effects of cannabinoid agonists. However, despite the widespread use and misuse of marijuana, and recognition of its potential adverse psychological effects in humans, comparatively few studies have examined the actions of its primary psychoactive constituent, delta(9)-tetrahydrocannabinol (THC), at well-defined synaptic pathways. Here we examine the recent literature describing the effects of acute and repeated THC exposure on synaptic function in several brain regions and explore the importance of these neurobiological actions of THC in drug addiction.
Cannabis has potential therapeutic use but tetrahydrocannabinol (THC), its main psychoactive component, appears as a risk factor for ischemic stroke in young adults. We therefore evaluate the effects of THC on brain mitochondrial function and oxidative stress, key factors involved in stroke. Maximal oxidative capacities V max (complexes I, III, and IV activities), V succ (complexes II, III, and IV activities), V tmpd (complex IV activity), together with mitochondrial coupling (V max/V 0), were determined in control conditions and after exposure to THC in isolated mitochondria extracted from rat brain, using differential centrifugations. Oxidative stress was also assessed through hydrogen peroxide (H2O2) production, measured with Amplex Red. THC significantly decreased V max (-71%; P<0.0001), V succ (-65%; P<0.0001), and V tmpd (-3.5%; P<0.001). Mitochondrial coupling (V max/V 0) was also significantly decreased after THC exposure (1.8+/-0.2 versus 6.3+/-0.7; P<0.001). Furthermore, THC significantly enhanced H2O2 production by cerebral mitochondria (+171%; P<0.05) and mitochondrial free radical leak was increased from 0.01+/-0.01 to 0.10+/-0.01% (P<0.001). Thus, THC increases oxidative stress and induces cerebral mitochondrial dysfunction. This mechanism may be involved in young cannabis users who develop ischemic stroke since THC might increase patient's vulnerability to stroke.
MDSCs are potent immunosuppressive cells that are induced during inflammatory responses, as well as by cancers, to evade the antitumor immunity. We recently demonstrated that marijuana cannabinoids are potent inducers of MDSCs. In the current study, we investigated the epigenetic mechanisms through which THC, an exogenous cannabinoid, induces MDSCs and compared such MDSCs with the naive MDSCs found in BM of BL6 (WT) mice. Administration of THC into WT mice caused increased methylation at the promoter region of DNMT3a and DNMT3b in THC-induced MDSCs, which correlated with reduced expression of DNMT3a and DNMT3b. Furthermore, promoter region methylation was decreased at Arg1 and STAT3 in THC-induced MDSCs, and consequently, such MDSCs expressed higher levels of Arg1 and STAT3. In addition, THC-induced MDSCs secreted elevated levels of S100A8, a calcium-binding protein associated with accumulation of MDSCs in cancer models. Neutralization of S100A8 by use of anti-S100A8 (8H150) in vivo reduced the ability of THC to trigger MDSCs. Interestingly, the elevated S100A8 expression also promoted the suppressive function of MDSCs. Together, the current study demonstrates that THC mediates epigenetic changes to promote MDSC differentiation and function and that S100A8 plays a critical role in this process.
Dronabinol is an orally active cannabinoid which, like other cannabinoids, has complex effects on the central nervous system (CNS), including central sympathomimetic activity. Cannabinoid receptors have been discovered in neural tissues. These receptors may play a role in mediating the effects of dronabinol and other cannabinoids.
For more Mechanism of Action (Complete) data for delta 9-Tetrahydrocannabinol (10 total), please visit the HSDB record page.
PharmacodynamicsPH
Dronabinol-induced sympathomimetic activity may result in tachycardia and/or conjunctival injection. Its effects on blood pressure are inconsistent, but subjects have experienced orthostatic hypotension and/or syncope upon abrupt standing. Dronabinol also demonstrates reversible effects on appetite, mood, cognition, memory, and perception. These phenomena appear to be dose-related, increasing in frequency with higher dosages, and subject to great inter-patient variability. After oral administration, dronabinol capsules have an onset of action of approximately 0.5 to 1 hour and a peak effect at 2 to 4 hours. Duration of action for psychoactive effects is 4 to 6 hours, but the appetite stimulant effect of dronabinol may continue for 24 hours or longer after administration. Tachyphylaxis and tolerance develop to some of the cardiovascular and CNS pharmacologic effects of dronabinol with chronic use, suggesting an indirect effect on sympathetic neurons. In a study of the pharmacodynamics of chronic dronabinol exposure, healthy male subjects (N = 12) received 12 times the maximum dose for anorexia associated with weight loss in patients with AIDS of dronabinol capsules in divided doses for 16 days. An initial tachycardia induced by dronabinol was replaced successively by normal sinus rhythm and then bradycardia. A decrease in supine blood pressure, made worse by standing, was also observed initially. These subjects developed tolerance to the cardiovascular and subjective adverse CNS effects of dronabinol within 12 days of treatment initiation. Tachyphylaxis and tolerance do not appear to develop to the appetite stimulant effect of dronabinol. In clinical studies of dronabinol capsules in AIDS patients, at the recommended dosage, the appetite stimulant effect was sustained for up to five months.
Pharmacokinetics
Half-lifePH
The elimination phase of dronabinol can be described using a two-compartment model with an initial (alpha) half-life of about 4 hours and a terminal (beta) half-life of 25 to 36 hours.
The elimination phase of dronabinol can be described using a two compartment model with an initial (alpha) half-life of about 4 hours and a terminal (beta) half-life of 25 to 36 hours.
After the pseudo-equilibrium is reached, THC is then slowly eliminated. This slow elimination is primarily due to the slow return of THC from sequestered tissues to blood. The terminal half-life of THC is approximately 1 day. /Several investigators have/ suggested terminal half-life /ranging between/ 19 to 36 hours. There are no significant differences in plasma profiles for chronic and infrequent users or in half-lives in moderate users before and after a 2-week exposure of THC.
The elimination half-life of dronabinol (delta-1-tetrahydrocannabinol) in 3 chronic marihuana users following smoking 4 cigarettes over a 2 day period is reported. The elimination half-life in blood plasma was calculated to be 4.1 days (range 2.9-5.0 days).
The terminal plasma half-life of metabolites from THC administration is approximately 50 hours, which is longer than that of THC. ... /Metabolites/
AbsorptionPH
Dronabinol is almost completely absorbed (90 to 95%) after a single oral dose. Due to the combined effects of first-pass hepatic metabolism and high lipid solubility, only 10 to 20% of the administered dose reaches systemic circulation. Relative bioavailability data from healthy male and female subjects suggest that a dose of 4.2 mg of SYNDROS provides comparable systemic exposure (Cmax and AUC) to a 5 mg dronabinol capsule, under fasted conditions, with the Cmax and AUCinf of 1.9 ± 1.3 ng/mL and 3.8 ± 1.8 ng.h/mL respectively. The concentrations of both dronabinol and its major active metabolite (11-hydroxy-delta-9-THC) peak at approximately 0.5 to 4 hours after oral dosing with SYNDROS and decline over several days. The mean inter- and intra-subject variability in dronabinol pharmacokinetics (Cmax and AUCinf) was approximately 66% and 47% and 67% and 14%, respectively, following the administration of SYNDROS to healthy subjects.
Dronabinol and its biotransformation products are excreted in both feces and urine. Biliary excretion is the major route of excretion with about half of a radiolabeled oral dose being recovered from the feces within 72 hours as contrasted with 10 to 15% recovered from urine. Less than 5% of an oral dose is recovered unchanged in the feces. Due to its redistribution, dronabinol and its metabolites may be excreted for prolonged periods of time. Following single-dose administration, dronabinol metabolites have been detected for more than 5 weeks in the urine and feces. In a study of dronabinol capsules involving AIDS patients, urinary cannabinoid/creatinine concentration ratios were studied bi-weekly over a six-week period. The urinary cannabinoid/creatinine ratio was closely correlated with the dose. No increase in the cannabinoid/creatinine ratio was observed after the first two weeks of treatment, indicating that steady-state cannabinoid levels had been reached. This conclusion is consistent with predictions based on the observed terminal half-life of dronabinol.
Dronabinol has a large apparent volume of distribution, approximately 10 L/kg, because of its lipid solubility.
The value for clearance average is about 0.2 L/kg-hr but is highly variable due to the complexity of cannabinoid distribution.
To establish a fast sensitive, reproducible LC-MS/MS method to study pharmacokinetic properties of THC, and compare relative bioavailability of THC and its solid dispersion in mice. 200 mice were divided randomly into two groups, and administered orally with THC and THC-solid dispersion after fasting (calculate on THC:400 mg x kg(-1)), used HPLC-MS/MS method to determine the THC concentration of each period at the following times: baseline ( predose ), 15, 30, 45 min, 1, 1.5, 2, 3, 4, 6, 24 hr after dosing. Calculating the pharmacokinetic parameters according to the C-t curv, and then use the Phoenix WinNonlin software for data analysis. The calibration curves were linear over the range 9.06-972 ug/L for THC (R2 = 0.999). The limit of detection (LOD) was 0.7 ug/L, respectively. The average extraction recoveries for THC was above 75%, The methodology recoveries were between 79% and 108%. The intra-day and inter-day RSD were less than 13%, the stability test showed that the plasma samples was stable under different conditions (RSD < 15%). The precision, accuracy, recovery and applicability were found to be adequate for pharmacokinetic studies. Pharmacokinetic parameters of THC and THC-solid dispersion orally to mice shows as fllows: T(max), were 60 and 15 min, AUC(0-t) were 44 00.43 and 57 497.81 mg x L(-1) x min, AUC(0-infinity) were 51226.00 and 68031.48 mg/L x min, MRT(0-infinity) were 596.915 6, 661.747 7 min, CL(z)/F were 0.007 809 and 0.005 88 L/min x kg. Compared with THC, the MRT and t1/2 of the THC-solid dispersion were all slightly extended, the t(max) was significantly reduced, AUC(0-24 hr), AUC(0-infinity) and C(max) were all significantly higher, the relative bioavailability of THC-solid dispersion is 1.34 times of THC. The results of the experiment shows that the precision, accuracy, recovery and applicability were found to be adequate for the pharmacokinetic studies. After oral administration to mice, the relative bioavailability of THC-solid dispersion show significant improvement compared to THC.
/MILK/ Marijuana has not been well studied, but tetrahydrocannabinol can reach rather high levels in /breast/ milk, particularly with heavy use. Although adverse effects in infants have not been reported, breast feeding should probably be avoided in heavy users and during therapeutic dronabinol use. Breast feeding should probably be withheld for several hr after occasional marijuana use. Caution should also be used to avoid exposing the infant to marijuana smoke.
MetabolismPH
THC is primarily metabolized in the liver by microsomal hydroxylation and oxidation reactions catalyzed by Cytochrome P450 enzymes. 11-hydroxy-▵9-tetrahydrocannabinol (11-OH-THC) is the primary active metabolite, capable of producing psychological and behavioural effects, which is then metabolized into 11-nor-9-carboxy-▵ 9-tetrahydrocannabinol (THC-COOH), THC's primary inactive metabolite. Dronabinol and its principal active metabolite, 11-OH-delta-9-THC, are present in approximately equal concentrations in plasma. Concentrations of both parent drug and metabolite peak at approximately 0.5 to 4 hours after oral dosing and decline over several days.
The analgesic activity of delta-8- and delta-9-THC is mainly due to the 11-hydroxy metabolite.
The metabolism of delta(9)-tetrahydrocannabinol (THC) is relatively complex, and over 80 metabolites have been identified. However, much less is known about the formation and fate of cannabinoid conjugates. Bile excretion is known to be an important route for the elimination of phase II metabolites. A liquid chromatography-tandem mass spectrometry LC-MS/MS procedure for measuring cannabinoids in oral fluid was adapted, validated and applied to 10 bile samples. THC, 11-hydroxy-delta(9)-tetrahydrocannabinol (11-OH-THC), 11-nor-9-carboxy-delta(9)-tetrahydrocannabinol (THCCOOH), cannabinol (CBN), cannabidiol (CBD), delta(9)-tetrahydrocannabinolic acid A (THC-A), 11-nor-9-carboxy-delta(9)-tetrahydrocannabinol glucuronide (THCCOOH-gluc) and delta(9)-tetrahydrocannabinol glucuronide (THC-gluc) were determined following solid-phase extraction and LC-MS/MS. High concentrations of THCCOOH-gluc were found in bile samples (range: 139-21,275 ng/mL). Relatively high levels of THCCOOH (7.7-1548 ng/mL) and THC-gluc (38-1366 ng/mL) were also measured. THC-A, the plant precursor of THC, was the only cannabinoid that was not detected. These results show that biliary excretion is an important route of elimination for cannabinoids conjugates and that their enterohepatic recirculation is a significant factor to consider when analyzing blood elimination profiles of cannabinoids. Furthermore, we suggest that the bile is the matrix of choice for the screening of phase II cannabinoid metabolites.
The presence of the metabolite 11-nor-9-carboxy-delta-9-tetrahydrocannabinol (C-THC) in hair is generally accepted as the definitive proof of delta-9-tetrahydrocannabinol (THC) ingestion. During hair analysis, the removal of any potential C-THC external contamination that could result from marijuana smoke or close personal contact via a wash procedure is critical. Here, we performed a series of experiments to demonstrate that C-THC is the reliable indicator of marijuana ingestion when paired with the correct washing procedure to remove potential external contamination.
Dronabinol undergoes extensive first-pass hepatic metabolism, primarily by microsomal hydroxylation, yielding both active and inactive metabolites. Dronabinol and its principal active metabolite, 11-OH-delta-9-THC, are present in approximately equal concentrations in plasma.
For more Metabolism/Metabolites (Complete) data for delta 9-Tetrahydrocannabinol (15 total), please visit the HSDB record page.
Protein bindingPH
The plasma protein binding of dronabinol and its metabolites is approximately 97%.
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