Two new clinical trials with THC and Cannabis in Europe
nova - Institute for Political and Ecological Innovation,
Thielstr. 35, D-50354, Hürth-Hermülheim, Germany
Both the Swiss and German governments have recently permitted controlled clinical tests of the benefits of oral synthetic THC and oral Cannabis extract for the treatment of spasticity, anorexia (loss of appetite) and cachexia (severe weight loss).
Rudolf Brenneisen, Ph.D., Professor at the Pharmaceutical Institute of the University of Bern (Switzerland) is planning a study with 20 patients suffering from spasticity. Robert Gorter, MD, Associate Professor at the University of California San Francisco's Medical School, and head of the Institute for Oncological and Immunological Research at Berlin's Moabit Hospital is planning a multi-center trial with several hundred AIDS and cancer patients suffering from anorexia and cachexia.
Spasticity and ataxia
An open-label pilot study involving two patients had been conducted in the course of the thesis of Andreas Egli in the Spring of 1994, under the guidance of both Dr. Brenneisen and Volker Henn, MD, Professor at the Neurological Clinic of the University of Zurich (Switzerland). Both patients suffered from severe spasticity due to myelopathia cervicalis and encephalomyelitis disseminata, respectively. The established drugs used for treating muscle spasms, which occur in the case of paraplegia, are often inefficient and cause serious side effects.
Synthetic delta-9-THC was applied orally in capsules (Dronabinol/Marinol ® ), as well as rectally in the form of suppositories (THC-hemisuccinate). The applied doses of THC were 0.1-0.2 mg/kg/day oral, and 0.025-0.075 mg/kg/day rectal, respectively. The aim of the study was to determine the equivalent doses and to compare the dose-effect relationships for the two methods of application. The patients served as their own controls and received THC either orally or rectally on four consecutive days. Patient A (77 kg) received 10 mg per os and 5 mg rectal (2:1), patient B (80 kg) 15 mg per os and 2.5 mg rectal (6:1). With rectal application, the "first pass effect" of the liver was diminished and the bio-availability was approximately doubled. Therefore similar or better effects were obtained with lower rectal doses, compared to oral application.
Pharmacokinetic (plasma samples) and objective (Ashworth-Scale, walking test) parameters, as well as subjective experience (patient protocol) were monitored and recorded. Both patients experienced a decrease in pain, spasticity and ataxia (movement disorders) as a function of the measured concentrations of THC in the plasma. During the study, patient A was able to decrease the dose of analgesics (metamizol) considerably. Patient B was, at times, able to walk without crutches. Psychotropic side effects were not observed at the applied doses.
A larger three-year spasticity trial, involving 20 patients, is planned to start during the Winter of 1996/97 and will be conducted as a double-blind placebo-controlled study at a center for paraplegia. One reason for conducting it at this clinic lies in the fact that marijuana has been extensively used by the center's patients in the past.
Anorexia and cachexia
Robert Gorter has participated in previous studies with AIDS and cancer patients in the USA. The results suggested a significant improvement of appetite and body weight, as well as an improvement in the general quality of life and diminution of nausea, when 2.5 mg of synthetic THC were administered twice daily. (Severe weight loss is an independent risk factor for morbidity and mortality.) These results led to the official acceptance of synthetic THC (Dronabinol/Marinol ® ) for the treatment of anorexia and cachexia in HIV-positives, AIDS and cancer patients by the U.S. Food and Drug Administration.
Table 1. Maximum daily plasma concentrations of synthetic delta-9-THC (ng/ml)
|Oral (10 mg THC)/Rectal (5 mg THC)||Oral (15 mg THC)/Rectal (2.5 mg THC)|
suggested that Cannabis is also, for these indications, at least as effective as
other drugs and causes less side effects. The German Federal Drug Administration
(Bundesopiumstelle, Berlin) recently permitted an efficacy (Phase II) trial proposed by
Gorter, which will compare the oral efficacy of both a THC-standardized extract of Cannabis
and synthetic delta-9-THC (Dronabinol/Marinol ® ). The study will be
conducted in several cities in Germany, Austria, Switzerland and the Netherlands as a
randomized, double-blind, placebo-controlled trial. An anticipated several hundred
patients will be split into three groups receiving different treatments. Following a
seven day baseline period, patients will receive 2.5 mg synthetic THC, a Cannabis extract
or a placebo twice daily. Their response will be monitored over an eight-week
period. In order to be able to participate in the study, patients must have lost at
least 5% of their normal body weight during the previous six months of their illness, and
be deemed suitable candidates for appetite stimulation. They must be able to consume
a standard diet without any restrictions.
The Cannabis to be used in the tests has been produced by HortaPharm B.V., an Amsterdam company which legally grows marijuana for research purposes. The processing of the Cannabis, to produce a THC-standardized oil extract, was also conducted at HortaPharm by Dr. Michael Werner and Mr. Christoph Jäggy of Switzerland's Forschungsinstitute Hiscia. The capsules will be manufactured in Germany.
It has been reported that THC may act as immune suppressant in HIV-positive individuals. Therefore, the concentration of certain T-lymphocytes (CD4) and the abundance of the HI-virus will also be determined in the course of the study. The participating patients will be asked to keep a daily diary, in which appetite, mood, sickness, as well as general quality of life will be measured and recorded using visual analog scales.
This study is planned to start in the Spring of 1997.