Single-dose Pharmacokinetics and Tolerability of Oral Delta-9- Tetrahydrocannabinol in Patients with Amyotrophic Lateral Sclerosis

Title:Single-dose Pharmacokinetics and Tolerability of Oral Delta-9- Tetrahydrocannabinol in Patients with Amyotrophic Lateral Sclerosis

Volume: 6 Issue: 2

Author(s): Markus Joerger, Justin Wilkins, Stefania Fagagnini, Reto Baldinger, Rudolf Brenneisen, Ursula Schneider, Bea Goldman and Markus Weber

Affiliation:

Keywords: Tetrahydrocannabinol, amyotrophic lateral sclerosis, pharmacokinetics, toxicity, absorption

Abstract: Background: Cannabinoids exert neuroprotective and symptomatic effects in amyotrophic lateral sclerosis (ALS). We assessed the pharmacokinetics (PK) and tolerability of delta-9-tetrahydrocannabinol (THC) in ALS patients.

Methods: Nine patients received THC single oral doses of 5mg and 10mg, separated by a wash-out period of two weeks. Blood samples for the determination of THC, 11-nor-9-carboxy-THC (THC-COOH) and hydroxy-THC (THC-OH) were taken up to 8 hours after intake. Adverse events were assessed by visual analogue scales (VAS). Plasma concentrations of the active metabolite THC-OH were submitted to sequential pharmacokinetic-pharmacodynamic population modeling on individual heart rate as a proxy for THC’s cardiovasculatory effects.

Results: Drowsiness, euphoria, orthostasis, sleepiness, vertigo and weakness were significantly more frequent in patients receiving 10mg compared to 5mg THC. A marked interindividual variability was found for the absorption of oral THC (84%) and elimination of THC-COOH (45%). PK data did not support any clinically relevant deviation from linear PK in the investigated range of concentrations. Plasma concentrations of THC-OH were positively correlated with the individual heart rate. An E_max-model was successfully fitted to individual heart rate, with a THC-OH plasma concentration of 3.2·10^-4 μmol/L for EC₅₀ and an E_max of 93 bpm for heart rate.

Conclusions: The higher 10mg dose of THC was dose-limiting in patients with ALS. High interindividual PK variability requires individuell titration of THC for potential therapeutic use in patients with ALS.

Cite this article as:

Joerger Markus, Wilkins Justin, Fagagnini Stefania, Baldinger Reto, Brenneisen Rudolf, Schneider Ursula, Goldman Bea and Weber Markus, Single-dose Pharmacokinetics and Tolerability of Oral Delta-9- Tetrahydrocannabinol in Patients with Amyotrophic Lateral Sclerosis, Drug Metabolism Letters 2012; 6 (2) . https://dx.doi.org/10.2174/1872312811206020102

DOI https://dx.doi.org/10.2174/1872312811206020102	Print ISSN 1872-3128
Publisher Name Bentham Science Publisher	Online ISSN 1874-0758