Jim Finnel
Fallen Cannabis Warrior & Ex News Moderator
Results from clinical research demonstrate that both dronabinol and whole plant cannabis can offer a safe and effective treatment for the following illnesses: muscle spasms in multiple sclerosis, Tourette syndrome, chronic pain, nausea and vomiting in HIV/AIDS and cancer chemotherapy, loss of appetite from cancer, hyperactivity of the bladder in patients with multiple sclerosis and spinal cord injury, and dyskinesia caused by levodopa in Parkinson's disease.
During the 1970’s and 1980’s, several states conducted research programs comparing smoked marijuana to oral forms of THC. Musty and Rossi reviewed the data from research programs in 6 states. The results from only one of these research programs had been published in peer-reviewed journals before 1995 (Vinciguerra et al. 1988). In their 2001 review, Musty and Rossi wrote:
"Data were available on 748 patients who smoked marijuana prior to and/or after cancer chemotherapy and 345 patients who used the oral THC capsule.. . . Patients who smoked marijuana experienced 70-100% relief from nausea and vomiting, while those who used the THC capsule experienced 76-88% relief. . . . On the basis of these studies, it appears that smoked marijuana can be a very successful treatment for nausea and vomiting following cancer chemotherapy.. . .The development of smokeless inhalation devices could certainly reduce the potential harm from smoking marijuana.” (Musti & Rossi 2001)
In an experimental study with 13 healthy volunteers, smoked cannabis was effective in reducing nausea and vomiting, but the 5-HT3 (serotonin) antagonist ondansetron was significantly more effective (Soderpalm et al. 2001). The study at the Department of Psychiatry of the University of Chicago examined the antiemetic effect of smoked marijuana cigarettes containing 8.4 and 16.9 mg THC compared to 8 mg ondansetron. Nausea and emesis were induced by syrup of ipecac. Marijuana significantly reduced ratings of nausea and slightly reduced the incidence of vomiting compared to placebo. Ondansetron completely eliminated the emetic effects of ipecac. These findings support and extend previous results, indicating that smoked marijuana reduces nausea and emesis. However, its effects were evaluated to be modest relative to the highly potent antiemetic drug ondansetron.
Delta-8-tetrahydrocannabinol (delta-8-THC), a cannabinoid with lower psychotropic potency than the main Cannabis constituent delta-9-THC, was administered at doses of 18 mg per square meter of body surface in edible oil, p.o., to eight children aged 3-13, undergoing cancer chemotherapy (Abrahamov et al. 1995). The children suffered from various hematologic cancers and were treated with different antineoplastic drugs for up to 8 months. The total number of treatments with delta-8-THC was 480. The THC treatment started two hours before each antineoplastic treatment and was continued every 6 hrs for 24 hours. Vomiting was completely prevented. Observed side effects from delta-8-THC observed were negligible.
THC (dronabinol) was not superior to megestrol acetate in improving appetite in cancer patients, according to a study published in January 2002 in the Journal of Clinical Oncology (Jatoi et al. 2002). U.S. and Canadian researchers found that 49 percent of those taking THC reported improved appetite, compared with 75 percent on megestrol acetate. Only 3 percent of the dronabinol group gained weight of more than 10 percent over baseline weight, compared with 11 percent following standard treatment with megestrol. A combination of both drugs did not improve the results received by megestrol acetate alone. Patients received either 800 mg megestrol acetate, 2 x 2.5 mg dronabinol, or both drugs. Overall, 469 cancer patients with weight loss had been enrolled in the study between December 1996 and December 1999. The study was conducted as a collaborative trial of the North Central Cancer Treatment Group and the Mayo Clinic.
Several new indications for cannabinoids have been and are under study, including neuroprotection in head trauma, antineoplastic effects for the treatment of cancers, effects against disturbed behavior in patients suffering from Alzheimer's disease, Tourette syndrom, and nausea and vomiting associated with HIV therapy.
Recent research showed that THC was not only effective in reducing nausea and vomiting associated with antineoplastic medication in cancer, but also reduced nausea and vomiting associated with HIV therapy (PRNewswire of 23 October 2000). This research by Roger Anderson and colleagues of Anderson Clinical Research in Pittsburgh was presented in October 2000 at the Fifth Congress on Drug Therapy in HIV Infection in Glasgow (Scotland). 85% (23/27) of HIV/AIDS patients who added dronabinol (THC), the most active cannabinoid, to their current antiretroviral therapy had a 50% improvement in symptoms of nausea and vomiting. The study enrolled patients who were on stable antiretroviral therapy. Twenty-seven patients were randomized to receive dronabinol 2.5 mg twice-daily within one hour of taking their antiretroviral medication (14 patients) or dronabinol 5.0 mg at bedtime (13 patients) for six weeks. At study start and at six weeks, patients were assessed by questionnaire for the number of minutes they did not feel well in the previous 48 hours, the number of episodes of vomiting, and the severity of nausea during the same period. Ninety-three percent (13/14) of patients in the group taking THC twice a day had a greater than 50% improvement in symptoms of nausea and vomiting, and 77% (10/13) of patients taking THC at bedtime had a greater than 50% improvement. The severity of nausea improved by at least one grade in 96% (26/27) of patients and no severe or very severe nausea was experienced in either group after six weeks.
Clinical research in patients with Tourette syndrome was stimulated by reports of patients that they had obtained relief from smoking cannabis. Research on the efficacy of dronabinol in Tourette syndrome included a study with one patient (Mueller-Vahl et al. 1999a), followed by a randomized double-blind placebo-controlled crossover trial of delta-9-THC in 12 adults (Mueller-Vahl et al. 1999b). In the larger study, patients received single doses of 5, 7.5, or 10.0 mg THC. Using both self and examiner rating scales, there was a significant improvement in motor and vocal tics after treatment with THC compared with placebo. In addition, a self-rating scale demonstrated a significant improvement in obsessive compulsive behaviour. No serious adverse reactions occurred. Five patients experienced transient mild side effects such as headache, nausea, dizziness, anxiety, cheerfulness, tremble, dry mouth, and hot flush. All these side effects did not last longer than 6 hours. There were no significant differences after treatment with THC compared with placebo in verbal and visual memory, reaction time, intelligence, sustained and divided attention, vigilance, and mood. These studies have already been followed by a successful six-week study (unpublished, personal communication Kirsten Mueller-Vahl, 2002). 17 patients completed the entire six-week program. In some participants, THC caused a considerable decrease of symptoms, thus confirming results of the earlier study. Side effects usually were mild even with a dosage of 10 mg THC.
Available preliminary data from research currently conducted in the UK with a cannabis extract that is taken sublingualy supports the analgesic effects of natural cannabis preparations in chronic pain from various causes (Notcutt et al. 2001a-c). A double blind "N of 1" study also showed that a cannabis extract containing equal amounts of THC and CBD was superior to THC with regard to side effects (Notcutt et al. 2001d). The main pain problems of a patient with multiple sclerosis were severe urethral pain and a pain deep within her pelvis. She achieved almost total pain control with the cannabis extract. Psychological side effects were predominantly seen during the periods when she used THC alone. During the periods when she used a 1:1 mixture of THC and CBD, the incidence of side-effects fell dramatically, compared to the same THC dose taken without CBD.
Preliminary results of clinical research conducted in the UK and in Switzerland show that cannabis and THC are able to reduce hyperactivity of the bladder in patients with multiple sclerosis and spinal cord injury (Hagenbach et al. 2001, Brady et al. 2001). The Swiss study conducted at the REHAB in Basel under the guidance of Ulrike Hagenbach includes 15 patients with spastic spinal cord injury who received oral or rectal THC (Hagenbach et al. 2001). Compared to placebo there was an improvement of some parameters of bladder activity, e.g. maximum capacity of the bladder (MCC, maximum cystometric capacity). The British study conducted at the National Hospital for Neurology and Neurosurgery in London under the guidance of Ciaran Brady and Clare Fowler included patients with advanced multiple sclerosis and problems with bladder function who received a sublingual cannabis spray. Maximum bladder capacity increased and frequency of need to urinate decreased both during day and night (Brady et al. 2001).
The therapy of Parkinson's disease using levodopa may cause dyskinesia, a movement disorder. In a pilot study with seven patients, a research group at the University of Manchester, Scotland, showed that nabilone, a synthetic THC derivative, significantly reduced levodopa-induced dyskinesia in patients with Parkinson's disease (Sieradzan et al. 2001).
In eight glaucoma patients resistant to conventional therapies, administering the synthetic cannabinoid-1-receptor agonist WIN55212-2 decreased the intraocular pressure by between 20 and 30% (Porcella et al. 2001). These data confirm that CB1 receptors that have been found in the ciliary body of the eye have direct involvement in the regulation of human intraocular pressure. THC binds to the CB1 receptor which explains the intraocular pressure lowering effects of cannabis.
In a Swiss study at the Clinic Montana under the guidance of Claude Vaney, the effects of capsulated cannabis extract in 57 patients with multiple sclerosis were investigated (Fortissimo 2002). In a crossover design, one half of the patients received a placebo first and then the extract, while the other half received cannabis first. The dose was adjusted according to individual tolerance. The maximal daily doses ranged from 7.5 to 30 mg THC. Muscle tone assessed with the Ashworth Scale was not significantly influenced by cannabis compared to placebo. However, subjectively the number of muscle spasms and the intensity of spasticity were reduced. Mobility as measured with the Rivermead-Mobility-Index (RMI) was improved with cannabis. Sleep was not significantly influenced. In general, the medication was tolerated well. Neither cognitive nor motor performance were significantly influenced by the cannabis medication.
Another study by a Dutch team using both a cannabis extract and THC in patients suffering from multiple sclerosis (MS) demonstrated that THC is not effective in MS when given in low oral doses of 2.5 or 5 mg oral twice daily (Killestein et al. 2002). In this double-blind, placebo-controlled study in 16 patients with MS who presented with severe spasticity, the safety, tolerability, and efficacy of oral THC and oral cannabis were investiagted. Compared with placebo, neither THC nor cannabis reduced spasticity at the doses applied (2.5 or 5 mg administered orally twice daily). Ungerleider et al. (1987) of the University of California in Los Angeles already noted in their 1987 study that "the 7.5 mg dose is required to achieve significant spasticity reduction" and in 1999 Pertwee recommended "a degree of flexibility with respect to dose level" in studies on THC in multiple sclerosis and to start with 2.5 or 5 mg twice daily.
All six neurosurgical intensive care units in Israel were involved in a double-blind, placebo-controlled study to evaluate the safety of intravenous dexanabinol in treating severe head injury (Knoller et al. 2002). 67 patients aged 16-65 years received a single administration of dexanabinol (48 or 150 mg) or only the vehicle. A highly significant reduction in the percentage of time during which pressure in the head of more than 25 mmHg occurred; perfusion pressure within the brain of below 50 mmHg and systolic blood pressure of below 90 mm Hg were observed in the drug-treated group. A trend toward faster and better neurological effect on the Glasgow outcome scale was also observed after 3 and 6 months. Dexanabinol is a non-psychotropic THC-derivative with neuroprotective properties. The neuroprotective properties of the natural plant cannabinoids THC and cannabidiol (CBD) are similar to those of dexanabinol (Hampson 2002).
Researchers at the Clinic for Anaesthesiology of the University of Cologne (Germany) reported their first experience with THC in pain management (Elsner et al. 2001). All patients treated with THC from February 1998 to January 2000 were evaluated. In six individuals suffering from chronic pain, THC was used in daily doses of 5-20 mg. Sufficient pain relief was achieved in three patients. The remaining three suffered from intolerable side effects such as nausea, dizziness and sedation without a reduction of pain intensity.
Overall recent clinical research shows that cannabis, THC and other agonists of the CB1 receptor are effective in a wide range of symptoms. Effectiveness may also vary widely among patients. THC or cannabis are often not the best medication available for one symptom but the combination of several of its effects may be very useful in a range of chronic illnesses that often present with several symptoms. This was clearly stated by the Institute of Medicine:
"In cases where symptoms are multifaced, the combination of THC effects might provide a form of adjunctive therapy; for example, AIDS wasting patients would likely benefit from a medication that simultaneously reduces anxiety, pain, and nausea while stimulating appetite" (Joy et al. 1999).
Thus, cannabis has been proposed for treatment of several diseases, among them amyotrophic lateral sclerosis and cystic fibrosis. Carter & Rosen (2001) of the University of Washington School of Medicine stated:
"Marijuana is a substance with many properties that may be applicable to the management of amyotrophic lateral sclerosis (ALS). These include analgesia, muscle relaxation, bronchodilation, saliva reduction, appetite stimulation, and sleep induction. In addition, marijuana has now been shown to have strong antioxidative and neuroprotective effects, which may prolong neuronal cell survival. In areas where it is legal to do so, marijuana should be considered in the pharmacological management of ALS. Further investigation into the usefulness of marijuana in this setting is warranted" (Carter & Rosen 2001).
Ester Fride (2002) analyzed the possible application of cannabis prepartions in the treatment of cystic fibrosis:
"Cannabis stimulates appetite and food intake. This property has been exploited to benefit AIDS and cancer patients suffering from wasting disease, by administering the whole plant or its active ingredient [delta-9]-tetrahydrocannabinol (THC). (...)
Lack of appetite resulting in malnutrition is a contributing factor to mortality in many Cystic Fibrosis patients. It is proposed here for the first time to administer THC to CF patients. It is hoped that the cannabinoid will alleviate malnutrition and thus help prevent wasting in CF patients. (...)
Recent findings suggest that a lipid imbalance (high arachidonic acid/low DHA) is a primary factor in the etiology of CF and that defective CFTR (CF transmembrane conductor regulator) that characterized the CF condition is responsible for the dysregulation. Endocannbinoids are all fatty acid derivatives. Therefore, it is further proposed here that the CFTR gene product also modulates endocannabinoids and by elevating these levels, symptoms may improve. Indeed, a number of physiological mechanisms of cannabinoids and endocannabinoids coincide with the pathology of CF. Thus it is suggested that potential benefits from THC treatment, in addition to appetite stimulation, will include antiemetic, bronchodilating, anti-inflammatory, anti-diarrheal and hypoalgesic effects” (Fride 2002).
Ethan Russo has examined marijuana’s potential in the treatment of migraines. His investigations show that modern neurological research lends new credibility to historical and anecdotal reports on the efficacy of cannabis in this area:
"Cannabis, or ‘marijuana,’ has been employed in various forms throughout the millennia for both symptomatic and prophylactic treatment of migraine.
In modern times, ethnobotanical and anecdotal references continue to support the efficacy of cannabis for headache treatment, while biochemical studies of THC and anandamide have provided scientific justification for its use via anti-inflammatory, serotonergic and dopaminergic mechanisms, as well as by interaction with NMDA and endogenous opioid systems. These are examined in detail.
The author feels that this collective evidence supports the proposition that experimental protocols of cannabis usage in migraine treatment should go forward employing modern controlled clinical trials” (Russo 2001).
A considerable number of clinical studies are under way to further study the effects of natural
cannabis preparations. (Source: Online Bulletins of the International Association for Cannabis as Medicine 1999-2002, International Association for Cannabis as Medicine (IACM))
Some of these studies are being conducted by GW Pharmaceuticals in the UK. By 2004, the company intends to obtain approval for a cannabis extract to be sprayed under the tongue. The main focus of this research is on chronic pain in patients with spinal cord injury, multiple sclerosis, nerve damage and cancer. GW Pharmaceuticals has expanded its studies to Canada. Under the guidance of the Institute for Oncological and Immunological Research in Berlin (Germany), a multicenter trial with several hundreds of patients is under way in Germany, Switzerland and Austria to test the effectiveness of an oral capsulated cannabis extract in comparison with THC in anorexia and cachexia of cancer patients. The same capsuled extract is used in a study with multiple sclerosis patients in the UK under the guidance of John Zajicek of Derriford Hospital, Plymouth. In total, 660 people will participate in the three-year program, which will involve 38 hospitals across Britain and is funded with £1.2 million pounds (U.S.$1.8 million) by the Medical Research Council (MRC). The study protocol was developed by the Royal Pharmaceutical Society of Great Britain.
A Center for Medicinal Cannabis Research has been set up at the University of California funded with several millions of dollars by the state, focusing on the use of marijuana in cancer and AIDS patients, but also for relieving spasticity and tremors in patients with multiple sclerosis. A study with smoked cannabis in neuropathy (nerve pain) associated with AIDS started under the guidance of Donald Abrams in San Fransisco. Initially, this pilot study, which began in March 2002, involves 16 volunteers. Each participant will stay in the hospital for nine days, smoking marijuana three times a day on seven of those days. If results of the pilot stady are encouraging, a larger study involving up to 100 subjects will follow. The study is double-blinded and uses THC free cannabis cigarettes as placebos. In San Diego, another researcher wants to examine how repeated treatment with cannabis affects driving ability of patients with HIV-related neuropathy or multiple sclerosis. The patients will be tested using a driving simulator. Another San Diego scientist will study how smoking marijuana might ease the uncontrollable muscle spasms and pain in multiple sclerosis.
In March 2002, a group of Spanish researchers started the first clinical study of cannabinoids in the treatment of cancer at the Hospital of La Laguna (Tenerife). The objective of the phase I-II trial is to evaluate the effects of THC on glioblastoma multiforme, a malignant brain tumor, for which there is currently no effective treatment. The study will be also the first study to investigate intracranial application of THC, an application directly into the brain. It will start with five patients. If the treatment is tolerated well, nine more patients will be added, divided into three groups, each receiving a different dose. THC will be administered for two to eight weeks and doses will depend on tolerance. Those patients will be selected whose tumors are accessible by means of surgery. The study is scheduled to last three years.
In 2002, the Office for Medicinal Cannabis of the Dutch Ministry of Health announced that it will conduct a clinical study on smoked cannabis in 16 multiple sclerosis patients. Results are expected to be available in the second half of 2003.
Health Minister Allan Rock, and Dr. Alan Bernstein, President of the Canadian Institutes of Health Research, announced on 26 July 2001 a Government of Canada contribution of $235,000 to fund a clinical study that will examine the therapeutic uses of cannabis. This is the first clinical trial related to the medical use of marijuana to be funded by Health Canada. Researchers at the Pain Centre of McGill University will conduct a one-year pilot study of smoked cannabis for chronic neuropathic pain at the General Hospital of Montreal. The study will also be the world's first peer-reviewed clinical trial examining the effects of smoked cannabis in a non-HIV or multiple sclerosis population. While other studies have tested the effects of cannabis constituents on pain, this will be the first trial in which participants will smoke the substance as outpatients.
This clinical research provides further evidence of that cannabis provides safe and effective treatment for several illnesses. Cannabis also has tremendous potential for the treatment of a wide variety of conditions as well.
References:
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Brady CM, DasGupta R, Wiseman OJ, Berkley KJ, Fowler CL. Acute and chronic effects of cannabis based medicinal extract on refractory lower urinary tract dysfunction in patients with advanced multiple sclerosis - early results. 2001 Congress on Cannabis and the Cannabinoids, Cologne, Germany: International Aaasociation for Cannabis as Medicine, p. 9,
Carter GT, Rosen BS. Marijuana in the management of amyotrophic lateral sclerosis. Am J Hosp Palliat Care 2001;18(4):264-70.
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Fride E. Cannabinoids and cystic fibrosis: a novel approach to etiology and therapy. J Cannabis Ther 2002;2(1);59-71.
Hagenbach U, Ghafoor N, Brenneisen R, Luz S, Maeder M. Clinical investigation of ?9-tetrahydrocannabinol (THC) as an alternative therapy for overactive bladders in spinal cord injury (SCI) patients. 2001 Congress on Cannabis and the Cannabinoids, Cologne, Germany: International Aaasociation for Cannabis as Medicine, p. 10.
Hampson A. Cannabinoids as neuroprotectants against ischemia. In: Grotenhermen F, Russo E, editors. Cannabis and cannabinoids. Pharmacology, toxicology, and therapeutic potential. Binghamton (NY): Haworth Press, 2002: 101-10.
Jatoi A, Windschitl HE, Loprinzi CL, Sloan JA, Dakhil SR, Mailliard JA, Pundaleeka S, Kardinal CG, Fitch TR, Krook JE, Novotny PJ, Christensen B. Dronabinol versus megestrol acetate versus combination therapy for cancer-associated anorexia: a North Central Cancer Treatment Group study. J Clin Oncol 2002;20(2):567-73.
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Killestein J, Hoogervorst EL, Reif M, Kalkers NF, Van Loenen AC, Staats PG, Gorter RW, Uitdehaag BM, Polman CH. Safety, tolerability, and efficacy of orally administered cannabinoids in MS. Neurology. 2002;58(9):1323-4.
Knoller N, Levi L, Shoshan I, Reichenthal E, Razon N, Rappaport ZH, Biegon A. Dexanabinol (HU-211) in the treatment of severe closed head injury: a randomized, placebo-controlled, phase II clinical trial. Crit Care Med 2002;30(3):710-1.
Mueller-Vahl KR, Kolbe H, Schneider U, Emrich H M: Cannabis in Movement Disorders. In: Grotenhermen F, Saller R (eds): Cannabis und Cannabinoide in der Medizin [Cannabis and Cannabinoids in Medicine]. Research in Complementary Medicine 6, Supplement 3, 1999b.
Mueller-Vahl KR, Schneider U, Koblenz A, Jobges M, Kolbe H, Daldrup T, Emrich HM. Treatment of Tourette-Syndrome with delta-9-tetrahydrocannabinol (THC): a randomized crossover trial. Pharmacopsychiatry 2002;35(2):57-61.
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Notcutt W, Price M, Miller R, Newport S, Sansom C, Simmonds S. Medicinal cannabis extracts in chronic pain: (5) cognitive function and blood cannabinoid levels. 2001c Congress on Cannabis and the Cannabinoids, Cologne, Germany: International Aaasociation for Cannabis as Medicine, p. 28
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During the 1970’s and 1980’s, several states conducted research programs comparing smoked marijuana to oral forms of THC. Musty and Rossi reviewed the data from research programs in 6 states. The results from only one of these research programs had been published in peer-reviewed journals before 1995 (Vinciguerra et al. 1988). In their 2001 review, Musty and Rossi wrote:
"Data were available on 748 patients who smoked marijuana prior to and/or after cancer chemotherapy and 345 patients who used the oral THC capsule.. . . Patients who smoked marijuana experienced 70-100% relief from nausea and vomiting, while those who used the THC capsule experienced 76-88% relief. . . . On the basis of these studies, it appears that smoked marijuana can be a very successful treatment for nausea and vomiting following cancer chemotherapy.. . .The development of smokeless inhalation devices could certainly reduce the potential harm from smoking marijuana.” (Musti & Rossi 2001)
In an experimental study with 13 healthy volunteers, smoked cannabis was effective in reducing nausea and vomiting, but the 5-HT3 (serotonin) antagonist ondansetron was significantly more effective (Soderpalm et al. 2001). The study at the Department of Psychiatry of the University of Chicago examined the antiemetic effect of smoked marijuana cigarettes containing 8.4 and 16.9 mg THC compared to 8 mg ondansetron. Nausea and emesis were induced by syrup of ipecac. Marijuana significantly reduced ratings of nausea and slightly reduced the incidence of vomiting compared to placebo. Ondansetron completely eliminated the emetic effects of ipecac. These findings support and extend previous results, indicating that smoked marijuana reduces nausea and emesis. However, its effects were evaluated to be modest relative to the highly potent antiemetic drug ondansetron.
Delta-8-tetrahydrocannabinol (delta-8-THC), a cannabinoid with lower psychotropic potency than the main Cannabis constituent delta-9-THC, was administered at doses of 18 mg per square meter of body surface in edible oil, p.o., to eight children aged 3-13, undergoing cancer chemotherapy (Abrahamov et al. 1995). The children suffered from various hematologic cancers and were treated with different antineoplastic drugs for up to 8 months. The total number of treatments with delta-8-THC was 480. The THC treatment started two hours before each antineoplastic treatment and was continued every 6 hrs for 24 hours. Vomiting was completely prevented. Observed side effects from delta-8-THC observed were negligible.
THC (dronabinol) was not superior to megestrol acetate in improving appetite in cancer patients, according to a study published in January 2002 in the Journal of Clinical Oncology (Jatoi et al. 2002). U.S. and Canadian researchers found that 49 percent of those taking THC reported improved appetite, compared with 75 percent on megestrol acetate. Only 3 percent of the dronabinol group gained weight of more than 10 percent over baseline weight, compared with 11 percent following standard treatment with megestrol. A combination of both drugs did not improve the results received by megestrol acetate alone. Patients received either 800 mg megestrol acetate, 2 x 2.5 mg dronabinol, or both drugs. Overall, 469 cancer patients with weight loss had been enrolled in the study between December 1996 and December 1999. The study was conducted as a collaborative trial of the North Central Cancer Treatment Group and the Mayo Clinic.
Several new indications for cannabinoids have been and are under study, including neuroprotection in head trauma, antineoplastic effects for the treatment of cancers, effects against disturbed behavior in patients suffering from Alzheimer's disease, Tourette syndrom, and nausea and vomiting associated with HIV therapy.
Recent research showed that THC was not only effective in reducing nausea and vomiting associated with antineoplastic medication in cancer, but also reduced nausea and vomiting associated with HIV therapy (PRNewswire of 23 October 2000). This research by Roger Anderson and colleagues of Anderson Clinical Research in Pittsburgh was presented in October 2000 at the Fifth Congress on Drug Therapy in HIV Infection in Glasgow (Scotland). 85% (23/27) of HIV/AIDS patients who added dronabinol (THC), the most active cannabinoid, to their current antiretroviral therapy had a 50% improvement in symptoms of nausea and vomiting. The study enrolled patients who were on stable antiretroviral therapy. Twenty-seven patients were randomized to receive dronabinol 2.5 mg twice-daily within one hour of taking their antiretroviral medication (14 patients) or dronabinol 5.0 mg at bedtime (13 patients) for six weeks. At study start and at six weeks, patients were assessed by questionnaire for the number of minutes they did not feel well in the previous 48 hours, the number of episodes of vomiting, and the severity of nausea during the same period. Ninety-three percent (13/14) of patients in the group taking THC twice a day had a greater than 50% improvement in symptoms of nausea and vomiting, and 77% (10/13) of patients taking THC at bedtime had a greater than 50% improvement. The severity of nausea improved by at least one grade in 96% (26/27) of patients and no severe or very severe nausea was experienced in either group after six weeks.
Clinical research in patients with Tourette syndrome was stimulated by reports of patients that they had obtained relief from smoking cannabis. Research on the efficacy of dronabinol in Tourette syndrome included a study with one patient (Mueller-Vahl et al. 1999a), followed by a randomized double-blind placebo-controlled crossover trial of delta-9-THC in 12 adults (Mueller-Vahl et al. 1999b). In the larger study, patients received single doses of 5, 7.5, or 10.0 mg THC. Using both self and examiner rating scales, there was a significant improvement in motor and vocal tics after treatment with THC compared with placebo. In addition, a self-rating scale demonstrated a significant improvement in obsessive compulsive behaviour. No serious adverse reactions occurred. Five patients experienced transient mild side effects such as headache, nausea, dizziness, anxiety, cheerfulness, tremble, dry mouth, and hot flush. All these side effects did not last longer than 6 hours. There were no significant differences after treatment with THC compared with placebo in verbal and visual memory, reaction time, intelligence, sustained and divided attention, vigilance, and mood. These studies have already been followed by a successful six-week study (unpublished, personal communication Kirsten Mueller-Vahl, 2002). 17 patients completed the entire six-week program. In some participants, THC caused a considerable decrease of symptoms, thus confirming results of the earlier study. Side effects usually were mild even with a dosage of 10 mg THC.
Available preliminary data from research currently conducted in the UK with a cannabis extract that is taken sublingualy supports the analgesic effects of natural cannabis preparations in chronic pain from various causes (Notcutt et al. 2001a-c). A double blind "N of 1" study also showed that a cannabis extract containing equal amounts of THC and CBD was superior to THC with regard to side effects (Notcutt et al. 2001d). The main pain problems of a patient with multiple sclerosis were severe urethral pain and a pain deep within her pelvis. She achieved almost total pain control with the cannabis extract. Psychological side effects were predominantly seen during the periods when she used THC alone. During the periods when she used a 1:1 mixture of THC and CBD, the incidence of side-effects fell dramatically, compared to the same THC dose taken without CBD.
Preliminary results of clinical research conducted in the UK and in Switzerland show that cannabis and THC are able to reduce hyperactivity of the bladder in patients with multiple sclerosis and spinal cord injury (Hagenbach et al. 2001, Brady et al. 2001). The Swiss study conducted at the REHAB in Basel under the guidance of Ulrike Hagenbach includes 15 patients with spastic spinal cord injury who received oral or rectal THC (Hagenbach et al. 2001). Compared to placebo there was an improvement of some parameters of bladder activity, e.g. maximum capacity of the bladder (MCC, maximum cystometric capacity). The British study conducted at the National Hospital for Neurology and Neurosurgery in London under the guidance of Ciaran Brady and Clare Fowler included patients with advanced multiple sclerosis and problems with bladder function who received a sublingual cannabis spray. Maximum bladder capacity increased and frequency of need to urinate decreased both during day and night (Brady et al. 2001).
The therapy of Parkinson's disease using levodopa may cause dyskinesia, a movement disorder. In a pilot study with seven patients, a research group at the University of Manchester, Scotland, showed that nabilone, a synthetic THC derivative, significantly reduced levodopa-induced dyskinesia in patients with Parkinson's disease (Sieradzan et al. 2001).
In eight glaucoma patients resistant to conventional therapies, administering the synthetic cannabinoid-1-receptor agonist WIN55212-2 decreased the intraocular pressure by between 20 and 30% (Porcella et al. 2001). These data confirm that CB1 receptors that have been found in the ciliary body of the eye have direct involvement in the regulation of human intraocular pressure. THC binds to the CB1 receptor which explains the intraocular pressure lowering effects of cannabis.
In a Swiss study at the Clinic Montana under the guidance of Claude Vaney, the effects of capsulated cannabis extract in 57 patients with multiple sclerosis were investigated (Fortissimo 2002). In a crossover design, one half of the patients received a placebo first and then the extract, while the other half received cannabis first. The dose was adjusted according to individual tolerance. The maximal daily doses ranged from 7.5 to 30 mg THC. Muscle tone assessed with the Ashworth Scale was not significantly influenced by cannabis compared to placebo. However, subjectively the number of muscle spasms and the intensity of spasticity were reduced. Mobility as measured with the Rivermead-Mobility-Index (RMI) was improved with cannabis. Sleep was not significantly influenced. In general, the medication was tolerated well. Neither cognitive nor motor performance were significantly influenced by the cannabis medication.
Another study by a Dutch team using both a cannabis extract and THC in patients suffering from multiple sclerosis (MS) demonstrated that THC is not effective in MS when given in low oral doses of 2.5 or 5 mg oral twice daily (Killestein et al. 2002). In this double-blind, placebo-controlled study in 16 patients with MS who presented with severe spasticity, the safety, tolerability, and efficacy of oral THC and oral cannabis were investiagted. Compared with placebo, neither THC nor cannabis reduced spasticity at the doses applied (2.5 or 5 mg administered orally twice daily). Ungerleider et al. (1987) of the University of California in Los Angeles already noted in their 1987 study that "the 7.5 mg dose is required to achieve significant spasticity reduction" and in 1999 Pertwee recommended "a degree of flexibility with respect to dose level" in studies on THC in multiple sclerosis and to start with 2.5 or 5 mg twice daily.
All six neurosurgical intensive care units in Israel were involved in a double-blind, placebo-controlled study to evaluate the safety of intravenous dexanabinol in treating severe head injury (Knoller et al. 2002). 67 patients aged 16-65 years received a single administration of dexanabinol (48 or 150 mg) or only the vehicle. A highly significant reduction in the percentage of time during which pressure in the head of more than 25 mmHg occurred; perfusion pressure within the brain of below 50 mmHg and systolic blood pressure of below 90 mm Hg were observed in the drug-treated group. A trend toward faster and better neurological effect on the Glasgow outcome scale was also observed after 3 and 6 months. Dexanabinol is a non-psychotropic THC-derivative with neuroprotective properties. The neuroprotective properties of the natural plant cannabinoids THC and cannabidiol (CBD) are similar to those of dexanabinol (Hampson 2002).
Researchers at the Clinic for Anaesthesiology of the University of Cologne (Germany) reported their first experience with THC in pain management (Elsner et al. 2001). All patients treated with THC from February 1998 to January 2000 were evaluated. In six individuals suffering from chronic pain, THC was used in daily doses of 5-20 mg. Sufficient pain relief was achieved in three patients. The remaining three suffered from intolerable side effects such as nausea, dizziness and sedation without a reduction of pain intensity.
Overall recent clinical research shows that cannabis, THC and other agonists of the CB1 receptor are effective in a wide range of symptoms. Effectiveness may also vary widely among patients. THC or cannabis are often not the best medication available for one symptom but the combination of several of its effects may be very useful in a range of chronic illnesses that often present with several symptoms. This was clearly stated by the Institute of Medicine:
"In cases where symptoms are multifaced, the combination of THC effects might provide a form of adjunctive therapy; for example, AIDS wasting patients would likely benefit from a medication that simultaneously reduces anxiety, pain, and nausea while stimulating appetite" (Joy et al. 1999).
Thus, cannabis has been proposed for treatment of several diseases, among them amyotrophic lateral sclerosis and cystic fibrosis. Carter & Rosen (2001) of the University of Washington School of Medicine stated:
"Marijuana is a substance with many properties that may be applicable to the management of amyotrophic lateral sclerosis (ALS). These include analgesia, muscle relaxation, bronchodilation, saliva reduction, appetite stimulation, and sleep induction. In addition, marijuana has now been shown to have strong antioxidative and neuroprotective effects, which may prolong neuronal cell survival. In areas where it is legal to do so, marijuana should be considered in the pharmacological management of ALS. Further investigation into the usefulness of marijuana in this setting is warranted" (Carter & Rosen 2001).
Ester Fride (2002) analyzed the possible application of cannabis prepartions in the treatment of cystic fibrosis:
"Cannabis stimulates appetite and food intake. This property has been exploited to benefit AIDS and cancer patients suffering from wasting disease, by administering the whole plant or its active ingredient [delta-9]-tetrahydrocannabinol (THC). (...)
Lack of appetite resulting in malnutrition is a contributing factor to mortality in many Cystic Fibrosis patients. It is proposed here for the first time to administer THC to CF patients. It is hoped that the cannabinoid will alleviate malnutrition and thus help prevent wasting in CF patients. (...)
Recent findings suggest that a lipid imbalance (high arachidonic acid/low DHA) is a primary factor in the etiology of CF and that defective CFTR (CF transmembrane conductor regulator) that characterized the CF condition is responsible for the dysregulation. Endocannbinoids are all fatty acid derivatives. Therefore, it is further proposed here that the CFTR gene product also modulates endocannabinoids and by elevating these levels, symptoms may improve. Indeed, a number of physiological mechanisms of cannabinoids and endocannabinoids coincide with the pathology of CF. Thus it is suggested that potential benefits from THC treatment, in addition to appetite stimulation, will include antiemetic, bronchodilating, anti-inflammatory, anti-diarrheal and hypoalgesic effects” (Fride 2002).
Ethan Russo has examined marijuana’s potential in the treatment of migraines. His investigations show that modern neurological research lends new credibility to historical and anecdotal reports on the efficacy of cannabis in this area:
"Cannabis, or ‘marijuana,’ has been employed in various forms throughout the millennia for both symptomatic and prophylactic treatment of migraine.
In modern times, ethnobotanical and anecdotal references continue to support the efficacy of cannabis for headache treatment, while biochemical studies of THC and anandamide have provided scientific justification for its use via anti-inflammatory, serotonergic and dopaminergic mechanisms, as well as by interaction with NMDA and endogenous opioid systems. These are examined in detail.
The author feels that this collective evidence supports the proposition that experimental protocols of cannabis usage in migraine treatment should go forward employing modern controlled clinical trials” (Russo 2001).
A considerable number of clinical studies are under way to further study the effects of natural
cannabis preparations. (Source: Online Bulletins of the International Association for Cannabis as Medicine 1999-2002, International Association for Cannabis as Medicine (IACM))
Some of these studies are being conducted by GW Pharmaceuticals in the UK. By 2004, the company intends to obtain approval for a cannabis extract to be sprayed under the tongue. The main focus of this research is on chronic pain in patients with spinal cord injury, multiple sclerosis, nerve damage and cancer. GW Pharmaceuticals has expanded its studies to Canada. Under the guidance of the Institute for Oncological and Immunological Research in Berlin (Germany), a multicenter trial with several hundreds of patients is under way in Germany, Switzerland and Austria to test the effectiveness of an oral capsulated cannabis extract in comparison with THC in anorexia and cachexia of cancer patients. The same capsuled extract is used in a study with multiple sclerosis patients in the UK under the guidance of John Zajicek of Derriford Hospital, Plymouth. In total, 660 people will participate in the three-year program, which will involve 38 hospitals across Britain and is funded with £1.2 million pounds (U.S.$1.8 million) by the Medical Research Council (MRC). The study protocol was developed by the Royal Pharmaceutical Society of Great Britain.
A Center for Medicinal Cannabis Research has been set up at the University of California funded with several millions of dollars by the state, focusing on the use of marijuana in cancer and AIDS patients, but also for relieving spasticity and tremors in patients with multiple sclerosis. A study with smoked cannabis in neuropathy (nerve pain) associated with AIDS started under the guidance of Donald Abrams in San Fransisco. Initially, this pilot study, which began in March 2002, involves 16 volunteers. Each participant will stay in the hospital for nine days, smoking marijuana three times a day on seven of those days. If results of the pilot stady are encouraging, a larger study involving up to 100 subjects will follow. The study is double-blinded and uses THC free cannabis cigarettes as placebos. In San Diego, another researcher wants to examine how repeated treatment with cannabis affects driving ability of patients with HIV-related neuropathy or multiple sclerosis. The patients will be tested using a driving simulator. Another San Diego scientist will study how smoking marijuana might ease the uncontrollable muscle spasms and pain in multiple sclerosis.
In March 2002, a group of Spanish researchers started the first clinical study of cannabinoids in the treatment of cancer at the Hospital of La Laguna (Tenerife). The objective of the phase I-II trial is to evaluate the effects of THC on glioblastoma multiforme, a malignant brain tumor, for which there is currently no effective treatment. The study will be also the first study to investigate intracranial application of THC, an application directly into the brain. It will start with five patients. If the treatment is tolerated well, nine more patients will be added, divided into three groups, each receiving a different dose. THC will be administered for two to eight weeks and doses will depend on tolerance. Those patients will be selected whose tumors are accessible by means of surgery. The study is scheduled to last three years.
In 2002, the Office for Medicinal Cannabis of the Dutch Ministry of Health announced that it will conduct a clinical study on smoked cannabis in 16 multiple sclerosis patients. Results are expected to be available in the second half of 2003.
Health Minister Allan Rock, and Dr. Alan Bernstein, President of the Canadian Institutes of Health Research, announced on 26 July 2001 a Government of Canada contribution of $235,000 to fund a clinical study that will examine the therapeutic uses of cannabis. This is the first clinical trial related to the medical use of marijuana to be funded by Health Canada. Researchers at the Pain Centre of McGill University will conduct a one-year pilot study of smoked cannabis for chronic neuropathic pain at the General Hospital of Montreal. The study will also be the world's first peer-reviewed clinical trial examining the effects of smoked cannabis in a non-HIV or multiple sclerosis population. While other studies have tested the effects of cannabis constituents on pain, this will be the first trial in which participants will smoke the substance as outpatients.
This clinical research provides further evidence of that cannabis provides safe and effective treatment for several illnesses. Cannabis also has tremendous potential for the treatment of a wide variety of conditions as well.
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