Dr. Rudolf Brenneisen
Rudolf Brenneisen is a Professor of Phytochemistry and Pharmacognosy in the Department of Clinical Research at the University of Bern, Switzerland. He is also Head of their Analytical Toxicology Unit and has engaged in research on plant products for over 20 years, including extensive investigations on Cannabis. Our interview was conducted by Dave Pate on February 5, 1997.
Can you give us something of your academic background?
Originally I was a pharmacist,
so I did study pharmaceutical sciences and after my Masters or my Federal Diploma, I
got a job offered at the Institute of Pharmacy of the University of Bern within the
department of phytochemistry and pharmacognosy. As part of my Ph.D. dissertation, I
did start an investigation on a Swiss medicinal plant, the blueberry in fact, studying the
tannin content vs. the stage of ripeness, etc. So it was a very traditional and
classical phytochemical work. I then decided to do something with pharmacologically
more active compounds, continuing as a Ph.D. I got a chance when my boss retired and
the faculty decided not to replace him, but to offer me an assistant professorship, a
position with teaching and research functions. So that was really the moment to
start my own projects and to do what Id like. I got financial assistance
because phytotherapy and phytochemistry is a main discipline within the pharmaceutical
sciences, as medicinal plants have a very long tradition in Switzerland.
And one day, the faculty said that for my academic career, it would be good to visit another university. So I decided that I would like to improve my Cannabis knowledge. I wrote a letter to Dr. ElSohly at the Research Institute of Pharmaceutical Sciences in Oxford Mississippi, and he said that I was most welcome to join his group and work on a very special Cannabis project. And that was the beginning of the chemical signature project which did really help to improve the analytical methodology and to get full chemical information on the Cannabis plant.
How long ago was that?
That was in 1987. I had the opportunity to work 6 months in Dr. ElSohlys lab, to have my own equipment, GC/MS and so on, 24 hours a day. And I didnt stop at night since I got really addicted to that topic!
How long have you had an interest in Cannabis and what is its origin?
A little bit more than 20 years, and my interest includes everything from forensics to therapeutic aspects. We once received a sample from the police. The question was how much THC was in that sample. Everybody in Switzerland said that a tropical climate is needed to produce a high-potency Cannabis plant with a high THC content, but I didnt believe that. So we performed an analytical monitoring, together with the police who confiscated a lot of homegrown material. And the result was that from a good hot summer, Cannabis plants can be produced that have a very reasonable THC content. I then needed someone who was a specialist in agriculture and, by coincidence, I met this kind of specialist who was looking for a laboratory person. That was the beginning of a really long project that began around 1980 and it did end with a very broad study concerning botanical, chemical and ecological aspects of Cannabis growing in Switzerland. We did study different seeds from different origins and concluded that in Switzerland, the climate is very well suited, providing that you cultivate an adapted variant. The highest content of THC was about 12% or so.
What do you think is the therapeutic potential of Cannabis, either as a whole drug or as a source of its component compounds?
I think both aspects are interesting and each has advantages and disadvantages. When you administer THC you can more precisely prepare the dosage and you know that the effect is caused by THC or a metabolite. But it costs a lot of money to prepare synthetic THC and administer it as Marinol®. If you prepare a standardized plant extract, you then have hundreds of compounds. Maybe THC is the main active cannabinoid, but you never know which compound in a complex mixture is responsible for the effect. Its more complicated to prove the exact mechanism of action. We know that there are receptors and that THC is going to the receptor, but do the other compounds influence absorption or pharmacokinetics, or interact with the receptor?
Do you have any indication of that?
We know from other medicinal plants that, for example, saponins enhance absorption through the gastrointestinal tract, so maybe there is the same situation with Cannabis, but there are no exact data because you have to measure blood levels and this is not so easy. We are in the process of doing that.
What would you say is the advantage of using Cannabis as a whole drug?
Production costs are lower. You dont have to isolate anything, you just prepare a simple crude extract. You measure the THC content or a total cannabinoid content and then standardize with some inert material, lactose or so. You may have a synergism with other compounds occurring in the plant. This is what we really know from other medicinal plants, but its not been studied in detail. Its a natural product, which is totally in the trend, at least in Europe, maybe not in The States. It is also something given by God and maybe this is a commercial aspect, but why not?
In Switzerland, there are major pharmaceutical companies that do care for phytotherapeutic products. Could you contrast the U.S. single-compound doctrine with the more flexible Swiss approach of anything that can be clinically validated and has a market?
We have two of the strongest pharmaceutical industries in the world: Novartis (resulting from the merger of Sandoz and Ciba-Geigy) and Roche. In fact the best products of the former Sandoz company and ones for which they are famous, are natural products, like the ergot alkaloids, although a couple years ago they decided to leave that area and invest money in other research projects. Anyway, the use of medicinal plants and natural products in Switzerland has a long tradition and if you go to a public pharmacy (and this is different in The States when you go to a drug store), you always find, really, at the very front, herbal teas, high quality herbal medicaments, standardized extracts, and pills with extracts. So this is very well accepted by the people. And the reasons are that we already have very strong synthetic pharmaceutical companies, the trend is Back to Nature and away from chemistry, and the big chemical disasters we had in, for example, northern Italy and in the Rhein River. All this, and a good marketing system, did help to establish and to increase the market for natural products. A couple years ago, one of the big pharmaceutical companies in Basle decided to enter that field and they did cooperate with a small, very recognized company who had a long tradition with medicinal plants and technology of preparation of extracts. So the best-sold products based on natural products are sold by one of the biggest pharmaceutical companies, Novartis. The line is called Valverde and everything is very professional, from standardized extract preparations to quality control to marketing. These products really help to promote medicinal plants.
So you would say that there is no apparent reason why plant-based drugs cant be used, assuming that the appropriate analytical controls are in place.
The problem is that you have to prove the efficacy and therapeutic value of natural products. Im not talking about homeopathics, because this is another story. For me, when you use qualitatively and quantitatively controlled natural products, there is absolutely no difference to a synthetic compound concerning registration. This is rational pharmacotherapy, nothing else. When you register, you must follow the same standards. The health authorities really demand the same standards, so there is no discrimination, nor any advantage because it is a natural product. So the same holds true for Cannabis products. If a company is ready to register, you need to provide data, the same protocol, and there is a good chance you can register a Cannabis extract.
What scale of study would be required, how complex and how rigorous? Would only a major pharmaceutical corporation be able to afford this or could a smaller university study be considered adequate?
You are talking about 2 to 3 hundred patients, maybe, for a big pharmaceutical company, or even thousands of patients. The difference is when you want to register a new substance, a new molecule, you have to follow Phase I toxicology studies. When you use a natural product with a long history, this is different. The registration authorities accept data from popular medicine, ethnopharmacological data from hundreds of years and this data may replace a big clinical study with hundreds of patients. Another reason why medicinal plants are quite popular is that we have two big societies: one European society for medicinal plant research and the other one is an association of Swiss physicians and pharmacists specialized in phytotherapy. So we already have an increasing group of physicians in Switzerland who are specialized in the administration and use of medicinal plants and most of these physicians are very open to Cannabis products.
Is medical Cannabis an issue in Switzerland? Is it medically controversial or is it seen as an offshoot of traditional medicine and therefore not so unacceptable?
First, THC is still an illegal substance. So the use of THC for clinical experiments and trials needs a special permit from the Federal Office of Public Health. We really have the privilege that our health authorities are very open to research projects, even with narcotics, not only with THC, if we really follow good clinical practice and use an ethically-approved study protocol. If not, you are out! Just now, the Swiss government has allowed private doctors to give THC as Marinol®, through us, to patients linked to a university research project. Meaning that when these people are linked to one of the university groups, they are able to get THC as a medicament, but only for research purposes, and within a clinical trial.
This is for what disease?
To reduce the muscle spasticity of both spinal cord injured and MS patients.
There isnt any Marinol® marketed commercially?
There is no registered THC product on the Swiss market, but to do clinical trials it is better to use a medicament that is approved by the US FDA, which is the most recognized authority. So for our trials we decided to use Marinol® vs. the suppositories prepared by Dr. ElSohly to compare the two administration routes.
And actually two different molecules?
Yeah, I must say that the THC in the suppositories is administered as the hemi-succinate ester. Its like a prodrug and has something to do with stability and absorption, etc.
What about the use of Cannabis in Switzerland as a medical agent, even if it isnt officially allowed. Do people do it anyway? Is there a popular movement in that direction?
When the media did hear about our project, they were very interested and made many reports on TV and radio. So a Swiss radio station conducted a survey of the Swiss population, looking for people who had experience with Cannabis as a medicament. I remember very well, for example, the mother who had a child suffering chronic migraine headache. No doctor could help, so she decided, along with her husband, to get some illegal Cannabis. She said, and not anonymously, but by name on the Swiss radio station, that the effect was just dramatic and the migraine attack was gone within minutes and the child was happy. What she administered was a Cannabis tea, which is also very astonishing since the bioavailability of cannabinoids from tea is low. Another example was a 70 year old patient with multiple sclerosis, who showed publicly on TV, how he prepared everyday his hashish medicament. Only with that illegal medicament is he able to treat his spasticity and to maintain a better quality of life. So these reports in the Swiss media really shocked, in a positive way, the Swiss population and it did really help us to go on with our Cannabis research projects. The Swiss government also recognized the need for this kind of research. We got the permit to go on with more patients and, just began two weeks ago, with a big study with patients paralyzed by spinal cord injuries from car accidents or sports, etc. In a big rehabilitation center in Switzerland, the physicians and the nurses observed that not only young patients, but also older ones smoke Cannabis. They have less spasticity problems and show a reduction of side effects with their other medicaments and can even reduce the dosage of these medicaments. So the MDs of that hospital decided to approach our group and ask for help in starting a big project in which the effect of THC, as Marinol® and as suppository, could be studied in a larger population of patients. This would also involve pharmacokinetics, doing blood and urine analysis. We introduced the placebo control and double-blind design in that study. The first study was only an open-label pilot study to establish the methodology for measuring the reduction of spasticity and mobility of two partly paralyzed patients. We measured, for instance, how much time they needed, with or without THC, to walk ten meters. It is a very simple test model to examine the effect of THC.
Based on what youve observed personally or heard from reliable sources, what would be the primary indication for the use of Cannabis as a medical drug?
We have only tested the indication of spasticity and the neurologists told me that spasticity is very often therapy-resistant, meaning that the classic medicaments stop working after a certain time or you have to increase the dosage. AIDS is another indication. THC increases appetite and the result is an increase in weight. So we are a part of this international and multi-center trial study of Dr. Gorter in Berlin. We just got the ethics permit to do a study at the oncology department at the University of Bern. Another very interesting indication is migraine and there are many, many reports about the effect of Cannabis products on migraine from popular medicine and anecdotal reports from people who use Cannabis products, including teas. That will be a future project and Ill really have the chance to collaborate with the best specialists for migraine therapy in Switzerland, working in the same university clinic where we did the first spasticity study. So many things are going on.
Its interesting that you mention migraine because in the United States, that indication is not brought up so much.
In the traditional Cannabis literature, you always find migraine. But I think no one has ever done a controlled clinical study. One reason might be that you really need a very, very careful patient evaluation and diagnosis. At least the specialist told me so, and migraine is not so easy to differentiate from other headaches. So it must be a classic migraine, but many migraine sufferers have written me and asked for help with Cannabis products. I remember the 50 year old woman who said that 350 days per year, she suffers from migraine and Cannabis is her last hope.
And this isnt just some little ache in the head, this a debilitating malady?
Every light and what you smell in the kitchen, every sensed thing is painful! So this women asked me for help. She said, I dont want to be illegal. I have experience with Cannabis products. My son can get it for me. Its not a problem of supply, you can get it everywhere in the city where Im living, but I dont want to be illegal and I dont want my son to be involved in an illegal act. So I have a whole collection of letters and telephone calls really motivating me to start this controlled clinical study with migraine patients.
Do you see any ethical problems with running a placebo-controlled Cannabis study with patients? Ive heard this point made, not because of Cannabis, but because of the placebo.
You are right, there are some ethical restrictions, but if you really want to publish the data in a reviewed journal, you need that design. Our first pilot study was not placebo controlled and the first journal, an American journal, refused to publish our open-label spasticity study with THC. But I think it was more a political reason. We had the same experience with another compound, psilocybin. Data from a pharmacokinetic study using that compound will be published in a good European journal. So, politics.
What about chemotherapy? Thats usually one of the most dramatic indications for Cannabis.
This does mean an increase in life quality, but I have a little problem with that indication. You reduce side effects of very strong medicaments. OK, why not? But new anti-emetic medicaments are now on the market which are very effective and you have always to prove that THC is better than what we already have and what is accepted and legal. I hear this very often when we have discussions with the health authorities. You must prove that THC is better concerning side effects, efficacy or safety, etc. If you dont do that, you have no chance for registration. The chief of the pharmaceutical department of the federal office of public health, who is responsible for the permits, told me he would be open-minded if a company came with good clinical and pharmaceutical data.
For a whole Cannabis product or an isolated compound?
At that time we were talking only about THC, but as I mentioned, we have a lot of well-established medicinal plant products, so it wouldnt seem so strange, providing it was a quality-controlled and state-of-the-art Cannabis preparation of proven therapeutic value.
What about the smoking aspect, or at least in a broader sense, the pulmonary application of THC or other cannabinoids vs. the gastrointestinal route?
The THC pill or the pill with Cannabis extract when taken orally, you lose too much of the THC (if we say this is the active compound) by a high liver metabolism, the first-pass effect. And intestinal absorption is not 100%. All this effects the content of THC in the blood.
Do you have a number for intestinal absorption? A figure of 10-15% is usually quoted.
The literature says THC has an oral bioavailability of 5-20%. We did a two patient study with THC in capsules. It was around 20-25%. We compared those with suppositories and the absorption rate, the bioavailability, was really much better, around 50%, double or so. And we understand that difference is mainly due to the first-pass effect. But to bring as much THC in a short time into the circulating blood system, the lungs are really the interesting site to absorb medicaments. The problem is that smoking, the traditional form of using Cannabis, is not an established pharmaceutical application form. So we have to find a way to inhale by a non-smoking technique, using a machine, a nebulizer or vaporizer, but our knowledge of this is at the very beginning. There are some technical problems, for example, to bring THC as a lipophilic compound in solution and to get particle size small enough to reach the deep compartments of the lungs, which is very important for a high absorption rate.
So in general, you think pulmonary application is superior, but there are some technical problems that have to be worked out.
Yes, I am convinced, as we have done inhalation experiments with other active compounds, such as opiates.
There are many more drugs that are given orally, or even as injectables, than there are those given by lung. Why do you think that in the history of general medical practice, it has been relatively rare that the lungs have been chosen as a route of administration?
An injection is always an invasive method linked to risk of contamination and infection and you need a person to give the injection. Except for a diabetic, the patient is not able to do that for himself. Swallowing a pill is easy. With inhalation, maybe there are more technological problems. I have no explanation why the lungs are not more used as an application site for medicaments, but at least the literature says that this will be for the future, a very interesting administration route. For example, maybe it could be used for peptides and compounds unstable in gastric acid. I am convinced that we have to spend more time and money to do the experiments with nebulizers and vaporizers or other techniques which deliver these compounds to the lungs.
What would you like to do if you had the appropriate funding?
I would do a comparison of synthetic THC with natural standardized Cannabis extracts for an indication like migraine. We really need good strong data. Another thing is to look and to develop other applications, other pharmaceutical preparations which should guarantee a high blood level of THC and be administered through the lungs. We know THC is well-absorbed from smoke, but we must replace the Cannabis cigarette, which is not accepted in medicine. The problem is to get THC in a solution which is compatible with the lungs and physiologically accepted. This will cost a lot of money, but maybe its not as difficult as some people think.