Single-dose Pharmacokinetics and Tolerability of Oral Delta-9- Tetrahydrocannabinol in Patients with Amyotrophic Lateral Sclerosis
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 Emax
-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 Emax
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.
Keywords: Tetrahydrocannabinol, amyotrophic lateral sclerosis, pharmacokinetics, toxicity, absorption
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