Cannabis has been promoted in the United States over the last 20 years as a means of relieving a wide range of conditions. It is said to provide relief for chronic states of pain, loss of appetite in the case of aids patients and cancer sufferers, nausea and vomiting (as a result of chemotherapy), asthma, glaucoma (increased internal pressure on the eye) and for sufferers of multiple sclerosis. Many marijuana users report that their symptoms are relieved, and that smoking this substance confers a feeling of well-being. As a result of referendum decisions, doctors in ten US states can now prescribe marijuana as a medicine. But various questions remain unanswered: - Is cannabis really effective? - Do we really take into account the cancer risk produced by smoking parts of a dried plant that contains hundreds of chemical substances, some of which are classed as carcinogenic? - Should we not wait until the active ingredient becomes available in a pure form, for administration by tablet or as drops? - What about the side-effects? - The main question is: Does cannabis fulfil the strict official guidelines on what constitutes an approved medical drug? Cannabinoids The terms “cannabis” and “marijuana” refer to the dried, unfertilized female flowers and leaves of the Indian hemp plant. The narcotic effect of the hemp plant is obtained from the 60 cannabinoids that it contains, particularly delta-9-tetrahydrocannabinol (THC), its biological precursor cannabidiol (CBD) and the THC decomposition product cannabinol (CBN). These substances stimulate the cannabinoid receptors in the central nervous system of the organism. The body’s on-board (endogenous) triggers for these receptors are called endocannabinoids, which play an important role in the modulation of many neuronal processes. Endogenous cannabinoids Human cannabis receptors CB1 and CB2 were discovered only 15 years ago. The human body possesses more CB1 receptors than dopamine, serotonin and noradrenaline. The endogenous substance that docks with these receptors to make them effective is anandamide. The role of anandamide receptor systems in the human body continues to be unclear. The largest number of CB1 receptors, to which anandamide and THC attach themselves, are found in the brain. CB1 receptors are located above all in the frontal lobes (responsible for motivation, planning) and in the basal ganglia and cerebellum (responsible for movement, coordination). In the limbic system, these receptors are present above all in the hypothalamus (regulation of food intake and body weight). Many of these receptors are also present in the hippocampus (memory). Their relatively low presence in the brain stem, from where the respiratory system is controlled, explains why it is not possible to die from an overdose of cannabinoids.
CB2 receptors are distributed around most of the body’s organs, with high concentrations in the spleen, the testicles and the immune cells. How the body absorbs cannabis Marijuana, or THC, can be taken in various ways: - Smoking leads to fast absorption by the body, with an immediately high plasma concentration. A particular disadvantage in this respect is the inhalation into the lungs of three times more tar than the equivalent in cigarettes. The results of smoking cannabis are somewhat comparable to those of heavy cigarette smoking. It can lead to lung diseases such as chronic bronchitis, phlegm, shortness of breath and whooping cough, apart from colds, inflammation of the lungs and lung cancer. - Synthetic THC in pill form, from an inhaler or as an oral spray: In order to avoid absorption of medicine by smoking, synthetic THC has been tested in pill form, and from an inhaler or oral spray. Marinol, a synthetic THC, has been approved in the USA as a prescription drug since 1985, as have Nabilone in the UK and Dronabinol in Germany. The drug can be used to combat the nausea suffered by cancer patients undergoing chemotherapy, and for stimulating the appetite of people suffering from aids. Studies show however that swallowed THC results in widely fluctuating levels of bioavailability, i.e. the amount of substance absorbed by the body cannot be predicted, and varies from person to person. A plant extract of cannabis has recently become available in the UK as an oral spray sold under the Sativex brand name. The bioavailability of Sativex is more constant than when the drug is delivered in tablet form. Compared to THC in tablet form, THC in suppository form delivers good bioavailability, constant plasma levels and thus greater effectiveness. Suppositories provide an ideal method of delivery for patients suffering from nausea and vomiting as a result of chemotherapy. However, no such preparation is yet available on the market. As soon as fat-soluble THC enters the body, it is taken up by fatty tissue for temporary storage. Its half-life period in the body (i.e. the time taken for half of the THC to be eliminated) is approximately one week. A long half-life period of this type makes dosage difficult, and brings with it a danger of accumulations of the substance in the body, resulting in symptoms of toxicity.
Development of new medicines The standards applied worldwide are, for good reason, very high when it comes to the approval of new substances designed for medical use. These norms are largely based on quality,safety and effectiveness. 1. Quality Requirements: development of constant forms of dosification covering the latest known compound. Clinical trials cannot be carried out without a constant form of dosification. All active ingredients must be identified, and their chemical properties must be known. The active ingredients must be tested for purity. There are maximum permitted levels with respect to impurities such as pesticides, bacteria and fungi, fertilizers and their products of decomposition. These tests must be recognized, and it must be possible to replicate them in any laboratory.
Cannabis contains over 400 chemical substances, in quantities that vary with the type of plant and method of cultivation. Many of these 400 substances are still unidentified. The concentrations of THC and other cannabinoids can also vary. For these reasons, it has to date not been possible to standardise the active ingredients. Cannabis is often contaminated with microbes, fungi, fertilizers and pesticides. All scientific articles on cannabis or THC criticize the fact that testing is carried out on substances of varying composition. Some studies have been carried out with cannabis, others with synthetic THC such as Marinol or Nabilone, with cannabinol or with intramuscular injections of levonantradol. 2. Safety The health consequences of smoking cannabis are serious, as is the danger of developing mental problems and addiction. - Physical health: The main risk is of damage to the lungs, as hundreds of carcinogenic substances are inhaled. This results in an increased risk of cancer of the respiratory organs and chronic lung damage. Cannabis in the form of synthetic THC also has undesired effects on the brain. This has resulted in such conditions as attention deficit and loss of memory and perception, with a negative effect on movement coordination. These side-effects also exert a harmful influence on driver behaviour and safety in the workplace. The long half-life period supposes heightened risk for persons who work, for example, with industrial or construction machinery, or in chemical plants or power stations. Further consequences of cannabis consumption include harm to the hormone and immune systems.
- Mental health: The smoking of cannabis can lead to general feeling of anxiety, loss of motivation, panic attacks, ideas of persecution, psychotic symptoms and the onset of schizophrenia. Cannabis use can lead both to the onset of schizophrenia in
persons so predisposed, or to a worsening of the symptoms in persons already suffering from this condition. - Dependency: Withdrawal symptoms can include restlessness, excitability, irritability, insomnia, nausea and muscular cramps. - Pregnancy/parenthood: The children of mothers who smoke cannabis during pregnancy suffer from stunted growth and have learning difficulties and behavioural problems, along with a ten-fold increased risk of contracting leukaemia. This is in addition to the problems that arise if parents are unable, as a result of their drug consumption, to act as effective guardians and educators. 3. Effectiveness The effectiveness of a substance is investigated accordingly in various clinical-test phases. These clinical tests are a vital prerequisite if a substance is to be approved for medicinal use. Clinical test phase I involves trials of the substance on healthy test subjects in order to study bodily absorption rates, bioavailability, half-life period and the speed at which the substance is eliminated from the body. Clinical test phase II is used to investigate the effect on patients with different symptoms and medical conditions in order to determine the most effective dose. In phase III, large groups of subjects are tested in order to reveal any statistically relevant factors. Control groups, which are given only a placebo or generic standard medicine, are also included in the testing process. The study must be randomized and double-blind. If all studies are successful, i.e. if the substance’s therapeutic properties are proven and there are no major problems with toxicity or serious undesired side-effects, the active ingredient is then recognised as a medicine and approved as such by the corresponding health authorities. Cannabis has not undergone these clinical-test phases, and has not been recognised as a medicine by any public health authority.Therefore, its use is not harmless, it is possibly of no benefit and it can be a health risk.
Literature on the subject Over 12,000 scientific articles have been published to date on the subject of cannabis. In 1998, the Institute for Medicine (IOM) published a summary of the essential elements of these articles, and this continues to be the most comprehensive report published on the subject to date. The report contains a critical analysis of the literature dealing with the effects of cannabis on the following symptoms and conditions: Chronic pain Trials on both animals and humans have shown that cannabinoids have a significant pain- killing effect, but there are no studies to show that they can replace conventional medicines. Chemotherapy-induced nausea and vomiting Compared with conventional treatments for these symptoms, the effect of cannabinoids can only be classed as moderate. Malnutrition, loss of weight and appetite Conventional medicines are more effective than cannabis for individual patients. Further development work and the clinical testing of fast-acting substances are recommended for such patients. Spastic symptoms of multiple sclerosis sufferers Existing clinical data are insufficient to allow statements as to whether cannabinoids are capable of relieving spastic paralysis (muscle cramping) for MS sufferers. Cannabis can alleviate spastic symptoms no more efficiently than a placebo. Epilepsy Current clinical knowledge is too incomplete to allow the recommending of cannabinoids for the treatment of epilepsy. Glaucoma The effectiveness of marijuana in the treatment of increased pressure on the interior of the eye, which leads to glaucoma, has only been demonstrated with very high doses. These high doses then result in the familiar side-effects of inhaling large amounts of smoke, leading to even greater problems elsewhere. The data submitted to the commission of experts revealed moderate therapeutic potential for cannabinoids in the treatment of pain, control of nausea and vomiting, and also of loss of appetite. But a range of good medicines, some of them excellent, already exists for the treatment of all the above symptoms and conditions. The commission recommended the conducting of clinical studies, ideally on animals to begin with, in order to obtain better data regarding the effect of cannabinoids on these conditions. The recommendation also included the carrying- out of randomised, double-blind studies, with a placebo control group, to determine the properties of individual cannabinoids.
Synthetic active ingredients The last few years have seen the discovery of a whole series of substances that have a stimulating or inhibiting effect on cannabis receptors. Several of these active ingredients are one day likely to be used, in combination with conventional medicines, to treat the above-mentioned conditions. The selection of substances listed in the box, all of which act on the endocannabinoid system, shows that we are just beginning with major developments in this field of new active ingredients for medicines. Rimonabant (Acomplia) is one these blockers that are shortly to be available as a medicine. It is designed to benefit the overweight, by stimulating the metabolism of fats, and also to help people give up smoking. It might also be of use in therapy for cannabis smokers, in the treatment of cravings and the prevention of relapses. Rimonabant is currently in phase II of its clinical trials as a treatment for alcoholism. Noladin, another endocannabinoid, binds with CB1 receptors and (weakly) with CB2 receptors. Effects: calming, reduction of body temperature, constipation and some pain- relieving effect when tested on mice. Virodhamine is a partial activator of CB1 receptors and a strong activator of CB2 receptors in the body. AM 1241, which binds above all with CB2 receptors, is being tested in animal trials for the treatment of several types of pain. This substance also helps to relieve the pain that accompanies chronic inflammation. It has no psychoactive effects, and is just as strong as morphine. HU-210, or Dexanabinol, is an activator found to have an effect 800 times stronger than THC when tested on mice, but without being psychoactive (i.e. it displays no psychological side- effects). HU-211, the enantiomer (mirror image) of HU-210, is currently in phase III of clinical testing as a medicine for use in the treatment of serious brain injuries. There are also a large number of substances that are known to reduce the readmittance of annandamide into the body’s cells, thus increasing its effects. These substances include AM- 404 and certain derivatives of cannabidiol. Cannabis is not a recognised medicine Neither reports on individual cases, nor self-reporting of experiences and clinical studies of small groups of patients using cannabis for medicinal purposes, have provided any conclusive proof of the effects of cannabis. The quality and format of these studies was defective, and no statistical evidence has been provided. The existing medicines prescribed for the same symptoms and conditions continue to display greater effectiveness than cannabis.
Cannabis fails, with respect both to quality and safety and in its effectiveness, to fulfil the high international standards and requirements that apply to recognition as a medicine. It cannot therefore be recommended as a therapeutic remedy. The risks and side-effects of inhaling plant material should not be underestimated, as it contains hundreds of partly-carcinogenic, toxic and unknown substances. The consequences are damage to the lungs and a heightened risk of cancer. The health risks inherent in taking such substances as medicine is high, and the psychological side-effects of THC, even in tablet form, are too serious to countenance its use as a prescription drug. The medical future of substances in this group lies in new, synthetically-produced drugs such as Rimonabant or Dexanabinol. Their main virtue is that they are not psychoactive and do not create dependence. The first medicines based on substances in this group will shortly be coming onto the market. Further specific substances are set to follow, subject to the same requirements regarding quality, safety and effectiveness. Dr. med. Hans Köppel
Mozafar Khazaei Ph.D [email protected] Associate Professor of Histology & Embryology Education: Fellowship (2003-2004) in Cell & Tissue Culture , Samuel lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Canada Ph.D. (1991-1995) in Anatomical Sciences, Medical Faculty, Isfahan University of Medical Sciences, Isfahan, Iran M.Sc . (
Extraction of Conditional Probabilities of the Relationships Between Drugs, Diseases, and Genes from PubMed Guided by Relationships in PharmGKB Martin Theobald, Ph.D1, Nigam Shah, M.B.B.S., Ph.D2, and Jeff Shrager, Ph.D3 Departments of (1) Computer Science, (2) Biomedical Informatics, Stanford University, Stanford, CA 94305 USA Abstract Suppose, for example, a patient is given