Pharmacokinetics and Tolerability of Δ9-THC-Hemisuccinate in a Suppository Formulation as an Alternative to Capsules for the Systemic Delivery of Δ9-THC, Mahmoud A. ElSohly et al., 2018,

Pharmacokinetics and Tolerability of Δ9-THC-Hemisuccinate in a Suppository Formulation as an Alternative to Capsules for the Systemic Delivery of Δ9-THC

Mahmoud A. ElSohly, Waseem Gul, Larry A. Walker

Medical Cannabis and Cannabinoids, 2018, 1, 44–53

Preclinical Science and Clinical Studies – Research Article

DOI: 10.1159/000489037



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 THCHS 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.

Keywords : Cannabinoids · Δ9-THC · Pharmacokinetics · THC metabolites · THC prodrugs · Suppository formulations



Δ9-Tetrahydrocannabinol (Δ9-THC) is the primary active ingredient of the plant Cannabis sativa L. (marijuana)and is responsible for the majority of the pharmacological effects of marijuana smoking. Marijuana has long been advocated for its medicinal value, and this is largely attributable to the activity of Δ9-THC. During cannabis smoking, rapid absorption of Δ9-THC occurs with smoking. Only seconds after the first puff from a Cannabis cigarette, Δ9-THC is detectable in plasma [1], with Cmax occurring 3–10 min after onset of smoking [2–6]. This accounts for the rapid euphoric effects of marijuana smoking or vapor inhalation, and experienced users will typically “titrate” the smoking rate to achieve thedesired effect. The delivery of Δ9-THC by other routes is delayed in onset and reduced in extent. However, in the context of therapeutics, smoking is a poor choice for delivery of Δ9-THC, as variability in consistency and quality of the botanical raw material and different smoking practices make it difficult to dose consistently. In addition, abuse liability and impairment risk must be considered. With smoking marijuana, the tars produced during this combustion process may be carcinogenic and can also injure the bronchial mucosa, decrease airway conductance, and impair the antibacterial activity of alveolar macrophages [7, 8]. One of the best established therapeutic actions of Δ9-THC is its remarkable effect on chemotherapy-induced nausea and vomiting. The endocannabinoid system, which mediates many of the pharmacological actions of Δ9-THC, is now known to be an important pathway in regulation of appetite and emesis [9–15]. Marinol® (orally administered dronabinol, the pharmaceutical name for Δ9-THC) was approved in the US in 1985 for the stimulation of appetite in AIDS-related anorexia and for chemotherapy-induced nausea and vomiting.

The appetite-stimulating effect of dronabinol for the treatment of AIDS-related anorexia was investigated in a randomized, double-blind, placebo-controlled study involving 139 patients [16]. As compared to placebo, dronabinol treatment resulted in a statistically significant improvement in appetite at 4 weeks. The study showed a sustained improvement in appetite for a full 12 months, without the need to increase the dose [17]. Dronabinol treatment of chemotherapy-induced nausea and vomiting was evaluated in 454 patients with cancer, who received a total of 750 courses of treatment for various malignancies [18].

Many other disease indications are also being explored for potential therapeutic benefits with Δ9-THC, including pain relief, spasticity in multiple sclerosis and spinal injury, posttraumatic stress disorder, and other neurological disorders [19–21].

Thus, these studies support the effectiveness of Δ9- THC for a number of indications. However, dronabinol oral absorption is slow and erratic, and the “first-pass” metabolic effect is high, so that when administered orally, there is a variable peak in Δ9-THC in plasma ranging from 45 min to a few hours, and an overall systemic bioavailability of about 10% [2, 22]. In addition to these pharmacokinetic considerations, the use of capsules in many of these indications can be limited by nausea, vomiting, or difficulty in swallowing. There are a number of alternatives for systemic delivery of Δ9-THC, including suppository administration. Studies in the first author’s laboratory (M.A.E.) over a number of years have established the feasibility of this approach. Since Δ9-THC is not absorbed rectally [2], prodrug formulations have been evaluated and, in animal studies, THC-hemisuccinate (THC-HS) was found to afford excellent potential for sustained delivery with good bioavailability and reduced “first-pass” metabolism [23]. The HS ester is absorbed across the rectal mucosa, but then hydrolyzes rapidly in plasma, releasing the active drug Δ9-THC. The bioavailability of Δ9-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 Δ9-THC, with relatively reduced first-pass metabolism, compared to oral administration [25].

The purpose of the present study is to more fully assess the tolerability and pharmacokinetics of ascending single doses of the THC-HS prodrug via suppository formulation in healthy human volunteers, and to compare the systemic delivery of Δ9-THC and its metabolism after oral administration of equivalent amounts as dronabinol capsules and via the prodrug in suppositories.