Article

Rectal Bioavailability of Δ-9-Tetrahydrocannabinol from the Hemisuccinate Ester in Monkeys

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Abstract

Oral administration of Δ-9-tetrahydrocannabinal (Δ9-THC) was shown to result in low and erratic bioavailability, while the drug showed no bioavailability from various suppository formulations. Δ9-THC-Hemisuccinate was formulated as a prodrug for Δ9-THC in suppositories using Witepsol H15 base. The bioavailability of Δ9-THC from this formulation was evaluated in monkeys. The plasma levels of Δ9-THC and its metabolite 11-nor-Δ9-THC-9-COOH were determined using GC/MS analysis. The calculated bioavailability of Δ9-THC from this formulation was found to be 13.5%. Non-compartmental analysis of the plasma concentration data using statistical moments showed the mean residence time (MRT) for Δ9-THC in the body to be 3 h following iv administration of Δ9-THC or its hemisuccinate ester (3.4 and 2.7 h, respectively), as compared with 5.8 h following rectal administration of the Δ9-THC hemisuccinate. The observed rectal bioavailability of Δ9-THC from suppositories containing the hemisuccinate ester as a prodrug is of significant importance in developing an alternative approach to oral administration of the drug.

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... The HS ester is absorbed across the rectal mucosa, but then hydrolyzes rapidly in plasma, releasing the active drug Δ 9 -THC. The bioavailability of Δ 9 -THC from THC-HS formulation in a Witepsol H15 base was demonstrated in monkeys [24]. A pilot study in 2 human subjects also suggested an improved systemic delivery of Δ 9 -THC, with relatively reduced first-pass metabolism, compared to oral administration [25]. ...
... The current study demonstrates that the delivery of Δ 9 -THC via a prodrug suppository formulation of the HS ester is well-tolerated in human volunteers, and supports a strategy to enhance systemic bioavailability and increase the duration of therapeutic plasma concentrations. Earlier animal studies [23,24] from our laboratory and a report from our collaborators on 2 human cases [25] suggested the potential utility of this approach. After oral administration, systemic bioavailability of Δ 9 -THC is sharply limited and variable because of delayed and erratic absorption and a prominent "first-pass" metabolism in the liver [22,26]. ...
Article
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The objectives of this study were: (1) to assess the safety, tolerability, and pharmacokinetics of ascending doses of Δ9-tetrahydrocannabinol-hemisuccinate (THC-HS) after rectal administration as suppositories in male volunteers; and (2) to compare the pharmacokinetics of oral administration of Δ9-tetrahydrocannabinol (Δ9-THC) with an equivalent amount of Δ9-THC delivered as THC-HS via the suppository formulation. In support of the pharmacokinetic evaluations, an analytical method was developed and validated for the determination of Δ9-THC and for its major circulating metabolites 11-hydroxy-Δ9-tetrahydrocannabinol (11-OH-THC) and 11-nor-Δ9-tetrahydrocannabinol-9-carboxylic acid (THC-COOH) in human plasma. Δ9-THC, 11-OH-THC, and THC-COOH were extracted from plasma using solid phase extraction and analyzed by liquid chromatography-tandem mass spectrometry. The limits of detection and quantitation for all 3 analytes were 0.25 and 0.5 ng/mL, respectively. The method was validated over the range of 0.5–25 ng/mL. This method was used to quantify Δ9-THC and any THC-HS as Δ9-THC due to the inclusion of a hydrolysis step as part of the extraction procedure. Therefore, Δ9-THC measured was the total THC (free Δ9-THC plus Δ9-THC derived from THC-HS). The assay was reproducible for the measurement of all 3 analytes, with a variability of 7.2, 13.7, and 8.3%, respectively, at the 1 ng/mL level. The method was then used to assess the pharmacokinetics of Δ9-THC and metabolites from the suppository dosage form in doses equivalent to 1.25, 2.5, 5, 10, and 20 mg Δ9-THC per suppository as THC-HS. Systemic exposure to Δ9-THC, administered as THC-HS suppository, increased broadly dose proportionally. Systemic exposure and Cmax (obs) estimates for 11-OH-THC and THC-COOH generally increased subproportionally. The pharmacokinetic profiles of Δ9-THC and metabolites were also compared after oral administration of 10 mg Δ9-THC (as dronabinol capsules) and after administration of 10 mg equivalents of Δ9-THC as THC-HS in suppository form. Total systemic exposure to Δ9-THC was considerably higher following rectal administration of THC-HS than after oral administration. The Δ9-THC area under the plasma concentration versus time curve (AUC(0–∞)) for THC-HS was 2.44-fold higher (90% confidence interval: 1.78, 3.35) than for the capsule administration.
... With rectal application, systemic bioavailability strongly differed depending on suppository formulations. Among formulations containing several polar esters of THC in various suppository bases, THChemisuccinate in Witepsol H15 showed the highest bioavailability in monkeys and was calculated to be 13.5% (ElSohly et al. 1991). The rectal bioavailability of this formulation in man was calculated to be about as twice as high (190-220%) as oral bioavailability in a small clinical study (Brenneisen et al. 1996). ...
Article
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Absorption and metabolism of tetrahydrocannabinol (THC) vary as a function of route of administration. Pulmonary assimilation of in-haled THC causes a maximum plasma concentration within minutes, while psychotropic effects start within seconds to a few minutes, reach a maxi-mum after 15 to 30 minutes, and taper off within 2 to 3 hours. Following oral ingestion, psychotropic effects set in with a delay of 30 to 90 minutes, reach their maximum after 2 to 3 hours, and last for about 4 to 12 hours, de-pending on dose and specific effect. The initial volume of distribution of THC is small for a lipophilic drug, equivalent to the plasma volume of about 2.5-3 L, reflecting high protein binding of 95-99%. The steady state volume of distribution has been esti-mated to be about 100 times larger, in the range of about 3.5 L per kg of body weight. The lipophility of THC with high binding to tissue and in par-ticular to fat, the major long-term storage site, causes a change of distribu-tion pattern over time. Only about 1% of THC administered IV is found in the brain at the time of peak psychoactivity. THC crosses the placenta and small amounts penetrate into the breast milk. Metabolism of THC occurs mainly in the liver by microsomal hydroxylation and oxidation catalyzed by enzymes of the cytochrome P-450 complex. In man, the C-11 carbon is the major site attacked. Hydroxylation results in 11-hydroxy-THC (11-OH-THC) and further oxi-dation to 11-nor-9-carboxy-THC (THC-COOH), which may be glucuronated to THC-COOH beta-glucuronide. Pharmacologically, 11-OH-THC shows a similar profile as THC while THC-COOH is devoid of psychotropic ef-fects. With oral administration higher amounts of 11-OH-THC are formed than with inhalation, reaching similar plasma levels as its parent drug, and contributing significantly to the overall effects of THC. Franjo Grotenhermen, MD, is affiliated with nova-Institut, Metabolic interaction between THC and the non-psychotropic canna-bidiol (CBD) is based on inhibition of the cytochrome P-450-3A enzyme by CBD. Repeated administration of all cannabinoids causes induction of some cytochrome P-450 isoenzymes which may result in interactions with other medical and non-medical drugs that are using the same enzymes for metabolism. [Article copies available for a fee from The Haworth Document De-livery Service: 1-800-HAWORTH.
... This stems from the significant limitations of traditional routes of drug administration. The non-parenteral routes under investigation include buccal (Li et al., 1997; Benes et al., 1997), sublingual (Cannon et al., 1996), rectal (ElSohly et al., 1991; Watanabe et al., 1996), nasal (Harris et al., 1988), and vaginal (Acarturk & Robinson, 1996). While each of these non-parenteral drug delivery routes has its associated advantages and disadvantages, the intra-oral transmucosal buccal route of drug administration has some unique benefits, including avoiding the first-pass effect, easy accessibility, and enhanced patient compliance. ...
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The purpose of this study was to determine and compare the bioadhesive profiles of hydroxypropylcellulose (HPC) polymer matrices as a function of delta9-tetrahydrocannabinol (THC) content. In addition, the effect of processing temperature on the stability of THC and its extent of degradation to cannabinol (CBN) was investigated. A hot-melt cast molding method was used to prepare HPC polymer matrix systems incorporated with THC at 0, 4, 8, and 16 percent. Bioadhesive measurements including peak adhesive force, area under the curve, and elongation at adhesive failure were recorded utilizing the TA.XT2i Texture Analyzer. Data obtained from these tests at various contact time intervals suggested that the incorporation of THC led to an increase in the bioadhesive strength of the HPC polymer matrices. To determine the stability of THC and the resulting CBN content in the matrices, three different processing temperatures were utilized (120, 160, and 200 degrees C). Post-production High Performance Liquid Chromotography (HPLC) analysis revealed that the processed systems contained at least 94% of THC and the relative percent formation of CBN was 0.5% at 120 degrees C and 0.4% at 160 degrees C compared to 1.6% at 200 degrees C. These findings indicate that the cannabinoid may be a plausible candidate for incorporation into systems utilizing hot-melt extrusion techniques for the development of an effective mucoadhesive transmucosal matrix system for delivery of THC.
... However, the results are ambiguous: Mattes et al. (1993) reported a 30-fold increase in bioavailability compared to Marinol ® in three females. Using the pro-drug THC-hemisuccinate ester resulted in a bioavailability of 13.5% (Elsohly et al., 1991b) or even 67% (Elsohly et al., 1991a), whereas in some cases THC was not absorbed at all (Perlin et al., 1985). Pulmonary administration circumvents first pass metabolism and THC is directly absorbed into the systemic blood circulation. ...
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The purpose of this study is to investigate whether spray freeze drying produces an inhalable solid dispersion powder in which Delta(9)-tetrahydrocannabinol (THC) is stabilised. Solutions of THC and inulin in a mixture of tertiary butanol (TBA) and water were spray freeze dried. Drug loads varied from 4 to 30 wt.%. Various powder characteristics of the materials were determined. Stability of THC was determined and compared with freeze dried material. The powders, dispersed with an inhaler based on air classifier technology, were subjected to laser diffraction analysis and cascade impactor analysis. Highly porous particles having large specific surface areas (about 90 m(2)/g) were produced. At high drug loads, THC was more effectively stabilised by spray freeze drying than by freeze drying. Higher cooling rates during spray freeze drying result in improved incorporation. Fine particle fractions of up to 50% were generated indicating suitability for inhalation. It was concluded that spray freeze drying from a water-TBA mixture is a suitable process to include lipophilic drugs (THC) in inulin glass matrices. High cooling rates during the freezing process result in effective stabilisation of THC. The powders can be dispersed into aerosols with a particle size appropriate for inhalation.
... Zurzeit findet der Versuch einer optimalen Sortenfindung statt, was sich angesichts der bestehenden eingeschränkten Verfügbarkeit als schwierig herausstellt. Des Weiteren soll auf eine nichtinhalative Applikation umgestellt werden: Angestrebt ist eine rektale Anwendung als Suppositorium mit der Wirksubstanz THC-Hemisuccinat [5,7,15]. Auf diese Weise soll der aufgrund der Bildung aktiver Metaboliten problematische First-Pass-Me-tabolismus umgangen werden. ...
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... GC-MS. The GC-MS procedure to test for the presence of 11-nor-carboxy-Ag-tetrahydrocannabinol-9-carboxylic acid (THCCOOH) was based on a previously published report for the analysis of marijuana in plasma (12). A standard curve was generated using a 5-point standard curve from 10 to 200 ng/mL. ...
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... During rectal administration, the bioavailability of cannabinoids is very discrepant, depending on the composition of the suppository [20]. A THC hemisuccinate suppository was the one with the highest bioavailability (13.5%) in monkeys [43]. In a study by Brenneisen et al. [44], where THC plasma concentrations were evaluated, it was found that after administration of 2.5 to 5 mg of THC, peak plasma concentrations ranged from 1.1 to 4.1 ng/mL and were reached between 2 h and 8 h, respectively. ...
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... D9-THC[36]. The rectal and oral bioavailability of D9-THC were calculated to be 13.5% and 5–20%, respectively[37]. The rectal bioavailability of D9THC is higher since avoid hepatic first pass effect, however, the bioavailability through this route fluctuates with different formulations[38]. ...
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... While Δ 9 -THC itself is not absorbed through the rectal route, the pro-drug Δ 9 -THC-hemisuccinate is absorbed; this fact, combined with decreased first-pass metabolism through the rectal route, results in a higher bioavailability of Δ 9 -THC by the rectal route (52 -61%) than by the oral route (293,294,295,296,297). Plasma concentrations of Δ 9 -THC are dose and vehicle-dependent, and also vary according to the chemical structure of the THC ester (296). ...
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... La biodisponibilité par cette voie dépend essentiellement de la formulation utilisée dans les suppositoires. Ainsi, le THC sous forme d'hémisuccinate dans du Witepsol H15 a présenté des valeurs maximales [19]. On estime dans ces conditions que la biodisponibilité est sensiblement le double de celle obtenue par voie orale [20] (Tableau 2). ...
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... Due to the significant limitations associated with traditional routes of administration, several non-parenteral routes have also been explored for systemic delivery of THC. These include sublingual [8], rectal [9], nasal [10] and transdermal [11]. With each of these routes having their own disadvantages, an attempt has been made to systemically deliver THC in the form of its novel prodrug, THC-HG through the oral transmucosal route, since it offers unique advantages including avoiding the first pass effect, easy accessibility and enhanced patient compliance. ...
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... 249 The prodrug Δ 9 -THC hemisuccinate is absorbed rectally rather than Δ 9 -THC, and this in combination with decreased first-pass metabolism leads to higher bioavailability of Δ 9 -THC (52-61%) as compared with the oral route. [249][250][251][252][253] Intramuscular and intravenous Δ 9 -THC has been evaluated in limited studies, 251,254 and the authors of 1 study involving monkeys suggested that intramuscular Δ 9 -THC may be a useful alternative route of administration, since it is more completely bioavailable as compared with the oral route. 251 ...
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Marijuana is a mixture of the flowers, stems, seeds and leaves of the hemp plant Cannabis, the primary psychoactive ingredient of which is Δ9-THC. Cannabinoids have two accepted medical uses in the United States, although many other potential medical uses are being considered. Marijuana is also the most commonly used illicit drug in the United States. It produces intoxicating effects when ingested, and higher doses are associated with psychedelic-like effects, such as an increased sensitivity to sound and a keener appreciation of rhythm and timing.
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Although Δ9-tetrahydrocannabinol (THC) has demonstrated utility for several medicinal applications, several studies have reported the inconsistent bioavailability of the oral soft gelatin capsule formulation, because of erratic absorption and variable first-pass metabolism of THC. This problem limits the utility of THC for its approved indications, and also prevents efficient assessment of other potential therapeutic applications. In an effort to overcome these pharmacokinetic limitations, we have explored the utility of various ester prodrugs of THC in suppository formulations as alternatives for effecting the systemic delivery of THC. Studies designed to characterize the bioavailability and efficacy of these preparations are reviewed here. In addition, studies designed to confirm the behavior of THC-hemisuccinate (THC-HS) as a prodrug were conducted. In rodents and dogs, intravenous administration of THC and THC-HS produced identical pharmacological responses (hypothermia and potentiation of thiamylal sleep times in mice; bradycardia in dogs) except at very high doses. Pharmacokinetic evaluations after intravenous and rectal administration of THC-HS also showed that the parent ester could not be detected in plasma, but that THC and its metabolite were detected in a fashion consistent with the immediate hydrolysis of THC-HS to THC in the absorption process or in the plasma. Administration of the THC-HS via suppositories resulted in excellent bioavailability, sustained plasma levels of THC, and improved efficacy as compared to the oral formulations, suggesting the feasibility of this route for the delivery of THC in various therapeutic applications.
Article
Medical cannabis, or cannabinoid-based products, continues to grow in popularity globally, driving the evolution of regulatory access frameworks; cancer patients and caregivers often rely on guidance from their physicians regarding cannabinoid-based treatments. But the majority of healthcare practitioners still feel unprepared and insufficiently informed to make reasonable, evidence-based recommendations about medical cannabis. More than 30 countries worldwide have now legalized access to medical cannabis; yet various nations still face arduous regulatory challenges to fulfill the needs of patients, healthcare practitioners, and other medical stakeholders. This has affected the deployment of comprehensive medical cannabis access programs adapted to cultural and social realities. With a 20-year history of legal medical cannabis access and nearly 400,000 registered patients under its federal access program, Canada serves as a model for countries which are developing their regulatory frameworks. The Canadian clinical experience in cannabinoid-based treatments is also a valuable source of lessons for healthcare professionals who wish to better understand the current evidence examining medical cannabis for oncology patients.
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The phytoconstituents of Cannabis sativa L. can be classified as pharmaceutical ingredients, nutrients, nutraceuticals, supplements, or herbal products. In the US the regulation of each constituent, in terms of veterinary use, is the responsibility of the Food and Drug Administration’s Center for Veterinary Medicine (FDA-CVM). In Canada these constituents and products are regulated by Health Canada. For designation as a pharmaceutical there is a lengthy and expensive approval process defined by the FDA-CVM and Health Canada Veterinary Drugs Directive (VDD) for animal drugs.
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Cannabis includes several species, the popular ones being Cannabis sativa, Cannabis indica, and Cannabis ruderalis. Cannabinoids are chemicals either derived from cannabis (phytocannabinoids) like cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC); synthetic medications like nabilone, dronabinol, and rimonabant; or endogenous chemicals that stimulate cannabinoid receptors. Cannabinoids have shown increasing evidence for analgesic effects in several studies and systematic reviews for acute and chronic pain (Meng et al. Anesth Analg. 125(5):1638–52, 2017) along with signs of becoming a potential alternative to combat opioid abuse (Olfson et al. Am J Psychiatry. 175(1):47–53, 2018). Phytocannabinoids are natural products derived from cannabis either interacting directly with cannabinoid receptors or sharing chemical similarity with endocannabinoids or both. Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), and cannabinol (CBN) are among the most studied phytocannabinoids. THC is the main psychoactive compound of the cannabis plant. Routes of administration (ROA) of THC range from vaporizing (inhalation), oral spray, edibles, other oromucosal/sublingual routes (e.g., capsules, oils, lozenges), transdermal topicals (cannabis-infused lotions, balms, oils), intravenous routes (syringe) to rectal routes (suppositories). Their applied pharmacology and pharmacokinetics differ greatly between different ROA. THC produces pharmacological effects ranging from cognitive changes and psychoactive, anti-inflammatory, antipruritic, bronchodilatory, anti-spasmodic, and muscle relaxant activities. It is also associated with side effects like anxiety, impaired memory, and immunosuppression. Further research and human studies are required to validate the role of THC for medicinal purposes.
Article
This research was conducted in order to fabricate stable polyethylene oxide (PEO)-based transmucosal systems of a Delta(9)-tetrahydrocannabinol (THC) prodrug, a hemisuccinate ester, using a hot-melt method. Since Delta(9)-tetrahydrocannabinol-hemisuccinate (THC-HS) was heat labile, a series of processing aids were evaluated in order to facilitate hot-melt production at lower temperatures, thereby reducing THC-HS degradation. The stability of THC-HS was influenced both by the processing conditions such as heating time and temperature, and the postprocessing storage conditions. The type of formulation additive also affected the extent of degradation. In the presence of polyethylene glycol (PEG)-400, the percentage of relative degradation of THC-HS to THC was 13.5% and 49.4% at 80 degrees C and 120 degrees C, respectively. In contrast, incorporation of vitamin E succinate (VES) reduced processing degradation to 2.1% and 9.2%, respectively, under the same conditions. Severe degradation of THC-HS was observed during storage, even under freezing conditions (-18 degrees C). A VES-Noveon AA-1 combination was observed to best stabilize the prodrug systems both during processing and postprocessing. Stabilization of THC-HS was achieved in these polyethylene oxide matrices at 4 degrees C, with almost 90% of theoretical drug remaining for up to 8 months. Investigation of the pH effect revealed that the pH of the microenvironment in these polymeric systems could be modulated to significantly improve the stability of THC-HS, degradation being the least in a relatively acidic medium.
Article
A microsuspension of Δ9-tetrahydrocannabinol and of its metabolic derivative 11-OH-Δ9-tetrahydrocannabinol has been prepared with 25 percent human serum albumin as the vehicle. Intravenous infusion of this preparation to humans indicates that both tetrahydrocannabinols are equally potent in producing the typical marihuana-like pschological and physiological effects.
Article
A comparative study was done in women and men of the effects of 9-tetrahydrocannabinol (9-THC), intravenously or orally, on dynamic activity, metabolism, excretion, and kinetics. In general no differences between the two sexes were observed. 9-THC is converted by microsomal hydroxylation to 11-hydroxy-9-THC (11-OH-9-THC), which is both a key intermediate for further metabolism to 11-nor-9-THC-9-carboxylic acid (11-nor-acid) by liver alcohol-dehydrogenase enzymes and a potent psychoactive metabolite. Major differences in the ratio of the concentration of 11-OH-9-THC to that of 9-THC in plasma were found after intravenous dosing (ratio 1:10 to 20) compared with oral administration (ratio 0.5 to 1:1). The final metabolic products are the 11-nor-acids and the related, more polar acids. Urinary excretion of 9-THC is restricted to acidic nonconjugated and conjugated metabolites. After 72 hr mean cumulative urinary excretion, noted for both routes and for both sexes, ranged from 13% to 17% of the total dose. After 72 hr the cumulative fecal excretion for both sexes after intravenous administration ranged from 25% to 30%; after oral administration the range was 48% to 53%. Metabolites were found in the feces in large concentration in the nonconjugated form; concentrations of 11-OH-9-THC were particularly noteworthy. Kinetics of 9-THC and metabolites were much the same for female and male subjects. For 9-THC, terminal-phase t½s for both sexes, irrespective of the route, ranged from 25 to 36 hr. A comparison of the results for AU C i dose (9-THC) after oral dosing with comparable data from intravenous administration indicated bioavailability of the order of 10% to 20% for both sexes. After intravenous 9-THC, large apparent volumes of distribution were noted (about 10 l/kg for both sexes).
Article
Oral Δ9-tetrahydrocannabinol (THC) in gelatin capsules is under evaluation as an antiemetic agent in cancer patients, but knowledge concerning its bioavailability is incomplete and, furthermore, alternative routes of administration may be desirable. In this study, the disposition of THC was determined in four rhesus monkeys given 2.5-mg/kg doses using the following routes of administration and formulations: intravenous (iv); orally (po) on a cookie and in gelatin capsules; intramuscularly (im) in Tween-80 and in Emulphor-EL620; rectally in various suppository bases. Serum THC concentrations were measured by RIA and analyzed by weighted nonlinear regression. Serum concentrations were best described by a sum of two exponentials with α and β half-lives (mean ± SD) of 0.74 ± 0.59 and 14.9 ± 12.5 h. Apparent bioavailability (%F ± SD) of various formulations of THC were: gelatin capsules, 26 ± 14; cookie, 89 ± 16; intramuscularly in Tween-80 and in Emulphor, 39 ± 13 and 102 ± 15, respectively. Using the method of statistical moments, mean residence times in the body (h ± SD) were: intravenous, 6.08 ± 1.60; cookie, 21.92 ± 3.11; gelatin capsule, 26.80 ± 23.61; intramuscularly in Emulphor, 10.92 ± 3.46 (in Tween-80, not calculated). THC was not bioavailable by the rectal route. We conclude from this study that THC formulated as a gelatin capsule exhibits a low and variable extent of bioavailability and that intramuscular THC may be a useful alternative route of administration since it is more completely bioavailable.
Article
Tissue levels of 3H were higher 2 hr after oral administration of 3H-delta9-THC (10 mg/kg in sesame oil) to male Fischer rats in the morning compared with treatment in the afternoon. A corresponding reduction in potency was seen for the impairing effect of delta9-THC on performance of a conditioned avoidance response (CAR). The hypothesis that these effects were related to the interval between feeding (which normally occurs during the night in the nocturnal rat) and drug administration was supported when they were mimicked in overnight fasted and ad lib fed rats. Food deprivation decreased the rate of gastrointestinal absorption of 14C-delta9-THC in sesame oil. Peak plasma levels of 14C occurred 2-4 hr after administration in fed rats compared with 8 hr in fasted rats. When tested 2 hr after oral administration, delta9-THC caused significantly greater impairment of CAR performance in fed than fasted rats, whereas the opposite was found after 8 hr. Extraction and subsequent thin layer chromatography of plasma and brain from fed and fasted rats sacrificed 2 or 8 hr after oral administration of 10 mg/kg 14C-delta9-THC showed that brain levels of 11-hydroxy-delta9-THC rather than delta9-THC were correlated with the behavioral effect.
Article
Anecdotal accounts suggested that smoking marihuana decreases the nausea and vomiting associated with cancer chemotherapeutic agents. Oral delta-9-tetrahydrocannabinol was compared with placebo in a controlled, randomized, "double-blind" experiment. All patients were receiving chemotherapeutic drugs known to cause nausea and vomiting of central origin. Each patient was to serve as his own control to determine whether tetrahydrocannabinol had an antiemetic effect. Twenty-two patients entered the study, 20 of whom were evaluable. For all patients an antiemetic effect was observed in 14 of 20 tetrahydrocannabinol courses and in none of 22 placebo courses. For patients completing the study, response occurred in 12 of 15 courses of tetrahydrocannabinol and in none of 14 courses of placebo (P less than 0.001). No patient vomited while experiencing a subjective "high". Oral tetrahydrocannabinol has antiemetic properties and is significantly better than a placebo in reducting vomiting caused by chemotherapeutic agents.
Article
Delta-9-tetrahydrocannabinol (THC) was given intravenously, by smoking, and by mouth to 11 healthy subjects. Plasma profiles of THC after smoking and intravenous injection were similar whereas plasma levels after oral doses were low and irregular, indicating slow and erratic absorption. Based on AUC0-360 min systemic availability of THC after smoking was estimated to be 18 +/- 6%. Oral THC in a chocolate cookie provided systemic availability of 6 +/- 3%. Of the two major clinical signs of cannabis intoxication, reddened conjunctivae persisted for as long as THC levels were above 5 ng/ml, and tachycardia was a less reliable measurement of prevailing THC levels or "high." The time courses of plasma concentrations and clinical "high" were of the same order for intravenous injection and smoking, with prompt onset and steady decline over a 4-hr period. The appearance of "high" lagged behind the increase in plasma concentrations, suggesting that brain concentrations were increasing as plasma concentrations decreased. After oral THC, the onset of clinical effects was much slower and lasted longer, but effects occurred at much lower plasma concentrations than after the other two methods of administration.
1.1. LD50's in mice after single intraperitoneal (i.p.) doses of cannabichromene (CBC) and Δ9-tetrahydrocannabinol (Δ9-THC) were 113.4 and 276.3 mg/kg, respectively. A small dose (25 mg/kg) of CBC given concurrently with Δ9-THC lowered the LD50 of Δ9-THC to 152.0 mg/kg.2.2. CBC, like Δ9-THC, caused hypothermia in mice; it reduced the effect of Δ9-THC at early times and increased it at later times after the two were injected simultaneously i.p.3.3. CBC and Δ9-THC, in 25 mg/kg i.p. doses, each prolonged hexobarbital hypnosis equally in mice, but had no additive effect in combination.