title: Single-dose pharmacokinetics and tolerability of oral delta-9- tetrahydrocannabinol in patients with amyotrophic lateral sclerosis.
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 5 mg 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 x 10(-4) μmol/L for EC(50) 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.
authors.affiliation: Medical Oncology & Clinical Pharmacology, Cantonal Hospital, Rorschacherstr. 95, 9007 St. Gallen, Switzerland. markus.joerger@gmail.com
authors.forename: Markus
authors.initials: M
authors.lastname: Joerger
authors.forename: Justin
authors.initials: J
authors.lastname: Wilkins
authors.forename: Stefania
authors.initials: S
authors.lastname: Fagagnini
authors.forename: Reto
authors.initials: R
authors.lastname: Baldinger
authors.forename: Rudolf
authors.initials: R
authors.lastname: Brenneisen
authors.forename: Ursula
authors.initials: U
authors.lastname: Schneider
authors.forename: Bea
authors.initials: B
authors.lastname: Goldman
authors.forename: Markus
authors.initials: M
authors.lastname: Weber
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy*; D063386:Cannabinoid Receptor Agonists / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D011446:Prospective Studies
chemical_list: D063386:Cannabinoid Receptor Agonists; C001427:11-hydroxy-delta(9)-tetrahydrocannabinol; C016780:11-nor-delta(9)-tetrahydrocannabinol-9-carboxylic acid; D013759:Dronabinol