Pharmacokinetics and analgesic potency of [Delta]9-tetrahydrocannabinol (THC)

It is known from the folk medicine that Cannabis may reduce pain. The aim of the pain study
was to compare analgesic effects of oral delta-9-tetrahydrocannabinol (THC, dronabinol,
Marinol‚, main psychoactive component of the Cannabis plant) and a THC-morphine
combination to morphine and placebo. This pain study was performed with 12 healthy
volunteers in four different experimental models of acute pain. Additionally, side effects and vital
functions were monitored and blood samples collected for the pharmacokinetic profiling of oral
THC. In none of the pain models THC showed a significant analgesic effect. The THC-morphine
combination showed a slight tendency to an additive effect compared to morphine alone, but
this was not statistically significant. The side effects observed with THC were mainly sleepiness
and mild to intermediate psychotropic side effects. The plasma concentrations of THC, analysed
with gas chromatography mass-spectrometry, were very low, showed a plasma peak time of 60
to 120 min with high inter-individual variation. In addition, an extensive liver first pass
metabolism could be observed leading to high metabolite-THC ratios.
In the second part of the present work the aim was to develop an application form as
alternative to the Marinol‚ capsules. The very lipophilic THC was solubilised with
Cremophor‚ RH 40 leading to a water-soluble THC formulation, which could be used as
inhalation solution for the pulmonal administration of THC. This formulation underwent an in
vitro quality assurance focussing on stability and physiological tolerability. Additionally, the
particle size of the droplets in the aerosol and the output rate of the evaluated nebuliser system
for the clinical application were determined.
In the third part of this work, the developed application form (inhalation solution) was used for
a second clinical study with eight healthy volunteers. The pharmacokinetic properties of
pulmonal THC were compared to intravenous THC and the analgesic effects were determined
comparing with pulmonal placebo. With the pulmonal application form the very low
bioavailability of oral THC could be increased up to 6-fold. Comparing the elimination half-lives,
a 5-fold decrease of the half-life after pulmonal and intravenous THC compared to oral THC
was observed, indicating that absorption is the time-determining step in the pharmacokinetic
behaviour of orally administered THC. This was also reflected by the peak plasma concentration
time, which occurred right at the end of the inhalation procedure of about 20 min (3 to 6-times
earlier than with oral THC). Peak plasma concentrations were much higher after pulmonal than
oral administration causing much less side effects, indicating that not only THC itself is
responsible for the psychotropic side effects but also the known strongly psychoactive 11-hydroxy-THC. Metabolite-THC ratios were found to be much lower after pulmonal and
intravenous THC than after oral THC.
The most prominent side effect of pulmonal THC was the irritation of the throat and coughing
during the inhalation, which were reversible within short time after finishing the inhalation
procedure.
Despite the increased bioavailability of pulmonal THC no analgesic effect resulted,
suggesting that the bioavailability does not affect the efficacy in the pain reducing properties of
THC. We assume that the used experimental pain models, which were all models of acute pain,
were not appropriate to study the analgesic properties of THC. Further experiments are needed
to evaluate the appropriate pain tests for THC and healthy subjects. In addition, it would be very
interesting to investigate the analgesic effect of the pulmonal THC in patients suffering from
chronic and neuropathic pain.