Jim Finnel
Fallen Cannabis Warrior & Ex News Moderator
Several scientific publications have reviewed evidence from research on the medicinal uses of cannabis indicating that cannabis in fact may offer benefits in the treatment of certain illnesses
Key quotes from five independent summaries of the medical benefits of the cannabinoid substances in marijuana are presented below. All of them refer to either “cannabis” or to “marijuana” specifically, and they all utilize the conceptual approach implied by Hollister in 2001 (Hollister 2001): clinical evidence on cannabinoids provides an understanding of the medical use of marijuana. The first article is by Grotenhermen, to be published in Clinical Pharmacokinetics in October 2002, the second by Williamson and Evans was published in the December 2000 issue of Drugs, the third is a review on “Therapeutic aspects of cannabis and cannabinoids” in 2001 by Robson that was commissioned by the British Government, the fourth review is an article by Glass, published in May 2001 in Progress in Neuro-Psychopharmacology and Biological Psychiatry, and the fifth is a review article by Porter and Felder in Pharmacological Therapeutics in April 2001.
Grotenhermen:
"Cannabis preparations have been employed in the treatment of numerous diseases, with marked differences in the available supporting data (BMA 1997, Grotenhermen and Russo 2002a, House of Lords 1998, Joy et al. 1999). Besides phytocannabinoids, several synthetic cannabinoid derivatives are under clinical investigation that are devoid of psychotropic effects, and modulators of the endocannabinoid system (re-uptake inhibitors, antagonists at the CB receptor, etc.) will presumably follow.
Hierarchy of Therapeutic Effects
Possible indications for cannabis preparations have been extensively reviewed (BMA 1997, Grinspoon and Bakalar, Grotenhermen 2002b, House of Lords 1999, Joy et al. 1999, Mathre 1997, Mechoulam 1986). To do justice to the scientific evidence with regard to different indications, a hierarchy of therapeutic effects can be devised, with established effects, relatively well-confirmed effects, less confirmed effects and a basic research stage. However the history of research into the therapeutic benefits of cannabis and cannabinoids has demonstrated that the scientific evidence for a specific indication does not necessarily reflect the actual therapeutic potential for a given disease, but sometimes obstacles to clinical research.
Established Effects
Marinol? (dronabinol) is approved for the medical use in refractory nausea and vomiting caused by antineoplastic drugs in cancer (Abrahamov et al. 1995, Dansak 1997, Lane et al. 1991, Sallan et al. 1980) and for appetite loss in anorexia and cachexia of HIV/AIDS patients (Beal et al. 1997, Plasse et al. 1991). These effects can be regarded as established effects for THC and cannabis. Cesamet™ (nabilone) is approved for nausea and vomiting associated with cancer chemotherapy.
Relatively Well-Confirmed Effects
Spasticity due to spinal cord injury (Brenneisen et al. 1996, Maurer et al. 1990, Petro 1980) and multiple sclerosis (Brenneisen et al. 1996, Meinck et al. 1989, Petro 1980, Petro and Elleberger 1981, Ungerleider et al. 1987), chronic painful conditions especially neurogenic pain (Elsner et al. 2001, Maurer et al. 1990, Notcutt et al. 2001a, Notcutt et al. 2001b, Noyes et al. 1975a, Noyes et al. 1975b), movement disorders (Clifford 1983, Hemming and Yellowlees 1993, Mueller-Vahl et al. 1999, Mueller-Vahl et al. 2002, Sandyk and Awerbuch 1998, Sieradzan et al. 2001), asthma (Hartley et al. 1978, Tashkin et al. 1974, Williams et al. 1976), and glaucoma (Crawford and Merritt 1979, Hepler and Frank 1971, Hepler and Petrus 1976, Merritt et al. 1980, Merritt et al. 1981) can be regarded as relatively well-confirmed effects with small placebo controlled trials demonstrating benefits. However, results were sometimes conflicting.
Less Confirmed Effects
There are several indications in which mainly only case reports suggest benefits. These are allergies (Schnelle et al. 1999), inflammation (Joy et al. 1999), epilepsy (Gordon and Devinsky 2001), intractable hiccups (Gilson and Busalacchi 1998), depression (Beal et al. 1995), bipolar disorders (Grinspoon and Bakalar 1998), anxiety disorders (Joy et al. 1999), dependency to opiates and alcohol (Mikuriya 1970, Schnelle et al. 1999), withdrawal symptoms ((Mikuriya 1970), and disturbed behaviour in Alzheimer's disease (Volicer et al. 1997).
Basic Research Stage
Basic research shows promising possible future therapeutic indications, among them neuroprotection in hypoxia and ischemia due to traumatic head injury, nerve gas damage and stroke (Hampson 2002, Mechoulam and Shohami 2002). Some immunological mechanisms of THC hint to possible benefits in basic mechanisms of T-helper 1 dominated autoimmune diseases, such as multiple sclerosis, arthritis, and Crohn's disease (Melamede 2002). Other fields of research are disorders of blood pressure (Ralevic and Kendall 2001, Wagner et al. 2001) and anti-neoplastic activity of cannabinoids (Jacobsson et al. 2001, Sanchez et al. 2001). Cannabinoids seem to be able to control the cell survival/death decision (Guzman et al. 2001). Thus cannabinoids may induce proliferation, growth arrest, or apoptosis in a number of cells depending on dose ((Guzman et al. 2001). Several effects observed in animal studies provide the basis for further research, among them effects against diarrhoea in mice (Izzo et al. 2000) and inhibition of bronchospasms provoked by chemical irritants in rats (Calignano et al. 2000).
Williamson:
“Cannabis has a potential for clinical use often obscured by unreliable and purely anecdotal reports. The most important natural cannabinoid is the psychoactive tetrahydrocannabinol (delta9-THC); others include cannabidiol (CBD) and cannabigerol (CBG). Not all the observed effects can be ascribed to THC, and the other constituents may also modulate its action; for example CBD reduces anxiety induced by THC. A standardised extract of the herb may be therefore be more beneficial in practice and clinical trial protocols have been drawn up to assess this. The mechanism of action is still not fully understood, although cannabinoid receptors have been cloned and natural ligands identified. Cannabis is frequently used by patients with multiple sclerosis (MS) for muscle spasm and pain, and in an experimental model of MS low doses of cannabinoids alleviated tremor. Most of the controlled studies have been carried out with THC rather than cannabis herb and so do not mimic the usual clinical situation. Small clinical studies have confirmed the usefulness of THC as an analgesic; CBD and CBG also have analgesic and anti-inflammatory effects, indicating that there is scope for developing drugs which do not have the psychoactive properties of THC. Patients taking the synthetic derivative nabilone for neurogenic pain actually preferred cannabis herb and reported that it relieved not only pain but the associated depression and anxiety. Cannabinoids are effective in chemotherapy-induced emesis and nabilone has been licensed for this use for several years. Currently, the synthetic cannabinoid HU211 is undergoing trials as a protective agent after brain trauma. Anecdotal reports of cannabis use include case studies in migraine and Tourette's syndrome, and as a treatment for asthma and glaucoma. Apart from the smoking aspect, the safety profile of cannabis is fairly good. However, adverse reactions include panic or anxiety attacks, which are worse in the elderly and in women, and less likely in children. Although psychosis has been cited as a consequence of cannabis use, an examination of psychiatric hospital admissions found no evidence of this, however, it may exacerbate existing symptoms. The relatively slow elimination from the body of the cannabinoids has safety implications for cognitive tasks, especially driving and operating machinery; although driving impairment with cannabis is only moderate, there is a significant interaction with alcohol. Natural materials are highly variable and multiple components need to be standardized to ensure reproducible effects. Pure natural and synthetic compounds do not have these disadvantages but may not have the overall therapeutic effect of the herb” (Williamson, 2000)
Robson:
“[This review [was] commissioned in 1996 by the Department of Health [of Great Britain] (DOH) [In order to] assess therapeutic profile of cannabis and cannabinoids. . . Cannabis and some cannabinoids are effective anti-emetics and analgesics and reduce intra-ocular pressure. There is evidence of symptom relief and improved well-being in selected neurological conditions, AIDS and certain cancers. Cannabinoids may reduce anxiety and improve sleep. Anticonvulsant activity requires clarification. Other properties identified by basic research await evaluation. Standard treatments for many relevant disorders are unsatisfactory. Cannabis is safe in overdose but often produces unwanted effects, typically sedation, intoxication, clumsiness, dizziness, dry mouth, lowered blood pressure or increased heart rate. The discovery of specific receptors and natural ligands may lead to drug developments. Research is needed to optimise dose and route of administration, quantify therapeutic and adverse effects, and examine interactions.” (Robson, 2001)
Glass:
“An understanding of the actions of Cannabis (Marijuana) has evolved from folklore to science over the previous hundred years. This progression was spurred by the discovery of an endogenous cannabinoid system consisting of two receptors and two endogenous ligands. This system appears to be intricately involved in normal physiology, specifically in the control of movement, formation of memories and appetite control. As we are developing an increased understanding of the physiological role of endocannabinoids it is becoming clear that they may be involved in the pathology of several neurological diseases. Furthermore an array of potential therapeutic targets is being determined--including specific cannabinoid agonists and antagonists as well as compounds that interrupt the synthesis, uptake or metabolism of the endocannabinoids. This article reviews the recent progress in understanding the contribution of endocannabinoids to the pathology and therapy of Huntington's disease. Parkinson's disease, schizophrenia and tremor.” (Glass, 2001)
Porter:
“The active principle in marijuana, Delta(9)-tetrahydrocannabinol (THC), has been shown to have wide therapeutic application for a number of important medical conditions, including pain, anxiety, glaucoma, nausea, emesis, muscle spasms, and wasting diseases. Delta(9)-THC binds to and activates two known cannabinoid receptors found in mammalian tissue, CB1 and CB2. The development of cannabinoid-based therapeutics has focused predominantly on the CB1 receptor, based on its predominant and abundant localization in the CNS. Like most of the known cannabinoid agonists, Delta(9)-THC is lipophilic and relatively nonselective for both receptor subtypes. Clinical studies show that nonselective cannabinoid agonists are relatively safe and provide therapeutic efficacy, but that they also induce psychotropic side effects. Recent studies of the biosynthesis, release, transport, and disposition of anandamide are beginning to provide an understanding of the role of lipid transmitters in the CNS. This review attempts to link current understanding of the basic biology of the endocannabinoid nervous system to novel opportunities for therapeutic intervention. This new knowledge may facilitate the development of cannabinoid receptor-targeted therapeutics with improved safety and efficacy profiles.” (Porter, 2001)
The above summaries provide overwhelming acceptance by the scientific and medical community that cannabis and single cannabinoids can offer therapeutic benefits in many conditions, at least for some of the patients. Recent research on the mechanisms of action of THC and other ligands of the cannabinoid receptor improves the understanding of these benefits and lends further support to this finding.
References
Abrahamov A, Abrahamov A, Mechoulam R. An efficient new cannabinoid antiemetic in pediatric oncology. Life Sci 1995; 56(23-24): 2097-102
Beal JE, Olson R, Laubenstein L, Morales JO, Bellman P, Yangco B, Lefkowitz L, Plasse TF, Shepard KV. Dronabinol as a treatment for anorexia associated with weight loss in patients with AIDS. J Pain Symptom Manage 1995;10(2):89-97.
Beal JE, Olson R, Lefkowitz L, Laubenstein L, Bellman P, Yangco B, Morales JO, Murphy R, Powderly W, Plasse TF, Mosdell KW, Shepard KV. Long-term efficacy and safety of dronabinol for acquired immunodeficiency syndrome-associated anorexia. J Pain Symptom Manage 1997; 14(1): 7-14
Brenneisen R, Egli A, Elsohly MA, Henn V, Spiess Y. The effect of orally and rectally administered delta 9-tetrahydrocannabinol on spasticity: a pilot study with 2 patients. Int J Clin Pharmacol Ther 1996; 34(10): 446-52
British Medical Association. Therapeutic uses of cannabis. Amsterdam: Harwood Academic Publishers, 1997.
Calignano A, Katona I, Desarnaud F, Giuffrida A, La Rana G, Mackie K, Freund TF, Piomelli D. Bidirectional control of airway responsiveness by endogenous cannabinoids. Nature 2000; 408(6808): 96-101
Clifford DB. Tetrahydrocannabinol for tremor in multiple sclerosis. Ann Neurol 1983; 13(6): 669-71
Crawford WJ, Merritt JC. Effects of tetrahydrocannabinol on arterial and intraocular hypertension. Int J Clin Pharmacol Biopharm 1979; 17(5): 191-6
Dansak DA. As an antiemetic and appetite stimulant in cancer patients. In: Mathre ML, editor. Cannabis in medical practice: A legal, historical and pharmacological overview of the therapeutic use of marijuana. Jefferson/NC: McFarland & Co, 1997: 69-83
Elsner F, Radbruch L, Sabatowski R. Tetrahydrocannabinol zur Therapie chronischer Schmerzen [Tetrahydrocannabinol for treatment of chronic pain]. Schmerz 2001; 15(3): 200-4.
Gilson I, Busalacchi M. Marijuana for intractable hiccups. Lancet 1998; 351(9098): 267
Glass M. The role of cannabinoids in neurodegenerative diseases. Prog Neuropsychopharmacol Biol Psychiatry 2001;25(4):743-65.
Gordon E, Devinsky O. Alcohol and marijuana: effects on epilepsy and use by patients with epilepsy. Epilepsia 2001; 42(10): 1266-72.
Grinspoon L, Bakalar JB. Marihuana, the forbidden medicine. New Haven: Yale University Press, 1993
Grinspoon L, Bakalar JB. The use of cannabis as a mood stabilizer in bipolar disorder: anecdotal evidence and the need for clinical research. J Psychoactive Drugs 1998: 30(2): 171-7
Grotenhermen F, Russo E, editors. Cannabis and cannabinoids. Pharmacology, toxicology, and therapeutic potential. Binghamton NY: Haworth Press, 2002a.
Grotenhermen F. Pharmacokinetics and pharmacodynamics of cannabinoids. Clin Pharmacokin, 2002, in press.
Grotenhermen F. Review of therapeutic effects. In: Grotenhermen F, Russo E, editors. Cannabis and cannabinoids. Pharmacology, toxicology, and therapeutic potential. Binghamton NY: Haworth Press, 2002b: 123-42
Guzman M, Sanchez C, Galve-Roperh I. Control of the cell survival/death decision by cannabinoids. J Mol Med 2001; 78(11): 613-25
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
Hartley JP, Nogrady SG, Seaton A. Bronchodilator effect of delta1-tetrahydrocannabinol. Br J Clin Pharmacol 1978; 5(6): 523-5
Hemming M, Yellowlees PM. Effective treatment of Tourette's syndrome with marijuana. J Psychopharmacol 1993; 7: 389-91.
Hepler RS, Frank IR. Marihuana smoking and intraocular pressure. JAMA 1971; 217(10): 1392
Hepler RS, Petrus RJ. Experiences with administration of marihuana to glaucoma patients. In: Cohen S, Stillman RC, editors. The therapeutic potential of marihuana. New York: Plenum Medical Book, 1976: 63-75
Hollister L. Marijuana (cannabis) as medicine. J Cannabis Ther 2001;1(1):5-27.
House of Lords Select Committee on Science and Technology. Cannabis. The scientific and medical evidence. London: The Stationery Office, 1998
Izzo AA, Pinto L, Borrelli F, Capasso R, Mascolo N, Capasso F. Central and peripheral cannabinoid modulation of gastrointestinal transit in physiological states or during the diarrhoea induced by croton oil. Br J Pharmacol 2000; 129(8): 1627-32
Jacobsson SO, Wallin T, Fowler CJ. Inhibition of rat C6 glioma cell proliferation by endogenous and synthetic cannabinoids. Relative involvement of cannabinoid and vanilloid receptors. J Pharmacol Exp Ther 2001; 299(3): 951-9
Joy JE, Watson SJ, Benson JA, editors. Marijuana and medicine: Assessing the science base. Washington DC: Institute of Medicine, National Academy Press, 1999
Lane M, Vogel CL, Ferguson J, Krasnow S, Saiers JL, Hamm J, Salva K, Wiernik PH, Holroyde CP, Hammill S, et al. Dronabinol and prochlorperazine in combination for treatment of cancer chemotherapy-induced nausea and vomiting. J Pain Symptom Manage 1991; 6(6): 352-9
Mathre ML, editor. Cannabis in medical practice: A legal, historical and pharmacological overview of the therapeutic use of marijuana. Jefferson, NC: McFarland & Co, 1997
Maurer M, Henn V, Dittrich A, Hofmann A. Delta-9-tetrahydrocannabinol shows antispastic and analgesic effects in a single case double-blind trial. Eur Arch Psychiatry Neurol Sci 1990; 240(1): 1-4
Mechoulam R, editor. Cannabinoids as therapeutic agents. Boca Raton: CRC Press, 1986
Mechoulam R, Shohami E. HU-211: Cannabinoid Neuroprotective Agent. In: Grotenhermen F, Russo E, editors. Cannabis and cannabinoids. Pharmacology, toxicology, and therapeutic potential. Binghamton (NY): Haworth Press, 2002: 389-400
Meinck HM, Schonle PW, Conrad B. Effect of cannabinoids on spasticity and ataxia in multiple sclerosis. J Neurol 1989; 236(2): 120-2
Melamede R. Possible mechanisms in autoimmune diseases. In: Grotenhermen F, Russo E, editors. Cannabis and cannabinoids. Pharmacology, toxicology, and therapeutic potential. Binghamton (NY): Haworth Press, 2002: 111-122
Merritt JC, Crawford WJ, Alexander PC, Anduze AL, Gelbart SS. Effect of marihuana on intraocular and blood pressure in glaucoma. Ophthalmology 1980; 87(3): 222-8
Merritt JC, Olsen JL, Armstrong JR, McKinnon SM. Topical delta 9-tetrahydrocannabinol in hypertensive glaucomas. J Pharm Pharmacol 1981; 33(1): 40-1
Mikuriya TH. Cannabis substitution. An adjunctive therapeutic tool in the treatment of alcoholism. Med Times 1970; 98(4): 187-91
Mueller-Vahl KR, Kolbe H, Schneider U, Emrich HM. Movement Disorders. In: Grotenhermen F, Russo E, editors. Cannabis and cannabinoids. Pharmacology, toxicology, and therapeutic potential. Binghamton (NY): Haworth Press, 2002: 205-214
Mueller-Vahl KR, Schneider U, Kolbe H, Emrich HM. Treatment of Tourette's syndrome with delta-9-tetrahydrocannabinol. Am J Psychiatry 1999; 156(3): 495
Notcutt W, Price M, Miller R, Newport S, Sansom C, Simmonds S. Medicinal cannabis extracts in chronic pain: (2) comparison of two patients with back pain and sciatica. 2001 Congress on Cannabis and the Cannabinoids, Cologne, Germany: International Aaasociation for Cannabis as Medicine, p. 25
Notcutt W, Price M, Miller R, Newport S, Sansom C, Simmonds S. Medicinal cannabis extracts in chronic pain: (3) comparison of two patients with multiple sclerosis. 2001 Congress on Cannabis and the Cannabinoids, Cologne, Germany: International Aaasociation for Cannabis as Medicine, p. 26
Noyes R Jr, Brunk SF, Avery DAH, Canter AC. The analgesic properties of delta-9-tetrahydrocannabinol and codeine. Clin Pharmacol Ther 1975a; 18(1): 84-9
Noyes R Jr, Brunk SF, Baram DA, Canter A. Analgesic effect of delta-9-tetrahydrocannabinol. J Clin Pharmacol 1975b; 15(2-3): 139-43
Petro DJ, Ellenberger C Jr. Treatment of human spasticity with delta 9-tetrahydrocannabinol. J Clin Pharmacol 1981; 21(8-9 Suppl): 413S-6S
Petro DJ. Marihuana as a therapeutic agent for muscle spasm or spasticity. Psychosomatics 1980; 21(1): 81, 85
Plasse TF, Gorter RW, Krasnow SH, Lane M, Shepard KV, Wadleigh RG. Recent clinical experience with dronabinol. Pharmacol Biochem Behav 1991; 40(3): 695-700
Porter AC, Felder CC. The endocannabinoid nervous system: unique opportunities for therapeutic intervention. Pharmacol Ther 2001;90(1):45-60.
Ralevic V, Kendall DA. Cannabinoid inhibition of capsaicin-sensitive sensory neurotransmission in the rat mesenteric arterial bed. Eur J Pharmacol 2001; 418(1-2): 117-25
Robson P. Therapeutic aspects of cannabis and cannabinoids. Br J Psychiatry 2001;178:107-15.
Sallan SE, Cronin C, Zelen M, Zinberg NE. Antiemetics in patients receiving chemotherapy for cancer: a randomized comparison of delta-9-tetrahydrocannabinol and prochlorperazine. N Engl J Med 1980; 302(3): 135-8
Sanchez C, de Ceballos ML, del Pulgar TG, Rueda D, Corbacho C, Velasco G, Galve-Roperh I, Huffman JW, Ramon y Cajal S, Guzman M. Inhibition of glioma growth in vivo by selective activation of the CB(2) cannabinoid receptor. Cancer Res 2001; 61(15): 5784-9
Sandyk R, Awerbuch G. Marijuana and Tourette's syndrome. J Clin Psychopharmacol 1998; 8: 844
Schnelle M, Grotenhermen F, Reif M, Gorter RW. Ergebnisse einer standardisierten Umfrage zur medizinischen Verwendung von Cannabisprodukten im deutschen Sprachraum, [Results of a standardized survey on the medical use of cannabis products in the German-speaking area]. 1999; (Suppl 3) 28-36. Forsch Komplementarmed [Res Complementary Med] 1999; (Suppl 3) 28-36
Sieradzan KA, Fox SH, Hill M, Dick JP, Crossman AR, Brotchie JM. Cannabinoids reduce levodopa-induced dyskinesia in Parkinson's disease: a pilot study. Neurology 2001; 57(11): 2108-11.
Tashkin DP, Shapiro BJ, Frank IM. Acute effects of smoked marijuana and oral ?9-tetrahydrocannabinol on specific airway conductance in asthmatic subjects. Am Rev Respir Dis 1974; 109(4): 420-8
Ungerleider JT, Andyrsiak T, Fairbanks L, Ellison GW, Myers LW. Delta-9-THC in the treatment of spasticity associated with multiple sclerosis. Adv Alcohol Subst Abuse 1987; 7(1): 39-50
Volicer L, Stelly M, Morris J, McLaughlin J, Volicer BJ. Effects of dronabinol on anorexia and disturbed behavior in patients with Alzheimer's disease. Int J Geriatr Psychiatry 1997; 12(9): 913-9
Wagner JA, Jarai Z, Batkai S, Kunos G. Hemodynamic effects of cannabinoids: coronary and cerebral vasodilation mediated by cannabinoid CB(1) receptors. Eur J Pharmacol 2001; 423(2-3): 203-10
Williams SJ, Hartley JP, Graham JD. Bronchodilator effect of delta1-tetrahydrocannabinol administered by aerosol of asthmatic patients. Thorax 1976; 31(6): 720-3
Williamson EM, Evans FJ. Cannabinoids in clinical practice. Drugs 2000;60(6):1303-14.
Key quotes from five independent summaries of the medical benefits of the cannabinoid substances in marijuana are presented below. All of them refer to either “cannabis” or to “marijuana” specifically, and they all utilize the conceptual approach implied by Hollister in 2001 (Hollister 2001): clinical evidence on cannabinoids provides an understanding of the medical use of marijuana. The first article is by Grotenhermen, to be published in Clinical Pharmacokinetics in October 2002, the second by Williamson and Evans was published in the December 2000 issue of Drugs, the third is a review on “Therapeutic aspects of cannabis and cannabinoids” in 2001 by Robson that was commissioned by the British Government, the fourth review is an article by Glass, published in May 2001 in Progress in Neuro-Psychopharmacology and Biological Psychiatry, and the fifth is a review article by Porter and Felder in Pharmacological Therapeutics in April 2001.
Grotenhermen:
"Cannabis preparations have been employed in the treatment of numerous diseases, with marked differences in the available supporting data (BMA 1997, Grotenhermen and Russo 2002a, House of Lords 1998, Joy et al. 1999). Besides phytocannabinoids, several synthetic cannabinoid derivatives are under clinical investigation that are devoid of psychotropic effects, and modulators of the endocannabinoid system (re-uptake inhibitors, antagonists at the CB receptor, etc.) will presumably follow.
Hierarchy of Therapeutic Effects
Possible indications for cannabis preparations have been extensively reviewed (BMA 1997, Grinspoon and Bakalar, Grotenhermen 2002b, House of Lords 1999, Joy et al. 1999, Mathre 1997, Mechoulam 1986). To do justice to the scientific evidence with regard to different indications, a hierarchy of therapeutic effects can be devised, with established effects, relatively well-confirmed effects, less confirmed effects and a basic research stage. However the history of research into the therapeutic benefits of cannabis and cannabinoids has demonstrated that the scientific evidence for a specific indication does not necessarily reflect the actual therapeutic potential for a given disease, but sometimes obstacles to clinical research.
Established Effects
Marinol? (dronabinol) is approved for the medical use in refractory nausea and vomiting caused by antineoplastic drugs in cancer (Abrahamov et al. 1995, Dansak 1997, Lane et al. 1991, Sallan et al. 1980) and for appetite loss in anorexia and cachexia of HIV/AIDS patients (Beal et al. 1997, Plasse et al. 1991). These effects can be regarded as established effects for THC and cannabis. Cesamet™ (nabilone) is approved for nausea and vomiting associated with cancer chemotherapy.
Relatively Well-Confirmed Effects
Spasticity due to spinal cord injury (Brenneisen et al. 1996, Maurer et al. 1990, Petro 1980) and multiple sclerosis (Brenneisen et al. 1996, Meinck et al. 1989, Petro 1980, Petro and Elleberger 1981, Ungerleider et al. 1987), chronic painful conditions especially neurogenic pain (Elsner et al. 2001, Maurer et al. 1990, Notcutt et al. 2001a, Notcutt et al. 2001b, Noyes et al. 1975a, Noyes et al. 1975b), movement disorders (Clifford 1983, Hemming and Yellowlees 1993, Mueller-Vahl et al. 1999, Mueller-Vahl et al. 2002, Sandyk and Awerbuch 1998, Sieradzan et al. 2001), asthma (Hartley et al. 1978, Tashkin et al. 1974, Williams et al. 1976), and glaucoma (Crawford and Merritt 1979, Hepler and Frank 1971, Hepler and Petrus 1976, Merritt et al. 1980, Merritt et al. 1981) can be regarded as relatively well-confirmed effects with small placebo controlled trials demonstrating benefits. However, results were sometimes conflicting.
Less Confirmed Effects
There are several indications in which mainly only case reports suggest benefits. These are allergies (Schnelle et al. 1999), inflammation (Joy et al. 1999), epilepsy (Gordon and Devinsky 2001), intractable hiccups (Gilson and Busalacchi 1998), depression (Beal et al. 1995), bipolar disorders (Grinspoon and Bakalar 1998), anxiety disorders (Joy et al. 1999), dependency to opiates and alcohol (Mikuriya 1970, Schnelle et al. 1999), withdrawal symptoms ((Mikuriya 1970), and disturbed behaviour in Alzheimer's disease (Volicer et al. 1997).
Basic Research Stage
Basic research shows promising possible future therapeutic indications, among them neuroprotection in hypoxia and ischemia due to traumatic head injury, nerve gas damage and stroke (Hampson 2002, Mechoulam and Shohami 2002). Some immunological mechanisms of THC hint to possible benefits in basic mechanisms of T-helper 1 dominated autoimmune diseases, such as multiple sclerosis, arthritis, and Crohn's disease (Melamede 2002). Other fields of research are disorders of blood pressure (Ralevic and Kendall 2001, Wagner et al. 2001) and anti-neoplastic activity of cannabinoids (Jacobsson et al. 2001, Sanchez et al. 2001). Cannabinoids seem to be able to control the cell survival/death decision (Guzman et al. 2001). Thus cannabinoids may induce proliferation, growth arrest, or apoptosis in a number of cells depending on dose ((Guzman et al. 2001). Several effects observed in animal studies provide the basis for further research, among them effects against diarrhoea in mice (Izzo et al. 2000) and inhibition of bronchospasms provoked by chemical irritants in rats (Calignano et al. 2000).
Williamson:
“Cannabis has a potential for clinical use often obscured by unreliable and purely anecdotal reports. The most important natural cannabinoid is the psychoactive tetrahydrocannabinol (delta9-THC); others include cannabidiol (CBD) and cannabigerol (CBG). Not all the observed effects can be ascribed to THC, and the other constituents may also modulate its action; for example CBD reduces anxiety induced by THC. A standardised extract of the herb may be therefore be more beneficial in practice and clinical trial protocols have been drawn up to assess this. The mechanism of action is still not fully understood, although cannabinoid receptors have been cloned and natural ligands identified. Cannabis is frequently used by patients with multiple sclerosis (MS) for muscle spasm and pain, and in an experimental model of MS low doses of cannabinoids alleviated tremor. Most of the controlled studies have been carried out with THC rather than cannabis herb and so do not mimic the usual clinical situation. Small clinical studies have confirmed the usefulness of THC as an analgesic; CBD and CBG also have analgesic and anti-inflammatory effects, indicating that there is scope for developing drugs which do not have the psychoactive properties of THC. Patients taking the synthetic derivative nabilone for neurogenic pain actually preferred cannabis herb and reported that it relieved not only pain but the associated depression and anxiety. Cannabinoids are effective in chemotherapy-induced emesis and nabilone has been licensed for this use for several years. Currently, the synthetic cannabinoid HU211 is undergoing trials as a protective agent after brain trauma. Anecdotal reports of cannabis use include case studies in migraine and Tourette's syndrome, and as a treatment for asthma and glaucoma. Apart from the smoking aspect, the safety profile of cannabis is fairly good. However, adverse reactions include panic or anxiety attacks, which are worse in the elderly and in women, and less likely in children. Although psychosis has been cited as a consequence of cannabis use, an examination of psychiatric hospital admissions found no evidence of this, however, it may exacerbate existing symptoms. The relatively slow elimination from the body of the cannabinoids has safety implications for cognitive tasks, especially driving and operating machinery; although driving impairment with cannabis is only moderate, there is a significant interaction with alcohol. Natural materials are highly variable and multiple components need to be standardized to ensure reproducible effects. Pure natural and synthetic compounds do not have these disadvantages but may not have the overall therapeutic effect of the herb” (Williamson, 2000)
Robson:
“[This review [was] commissioned in 1996 by the Department of Health [of Great Britain] (DOH) [In order to] assess therapeutic profile of cannabis and cannabinoids. . . Cannabis and some cannabinoids are effective anti-emetics and analgesics and reduce intra-ocular pressure. There is evidence of symptom relief and improved well-being in selected neurological conditions, AIDS and certain cancers. Cannabinoids may reduce anxiety and improve sleep. Anticonvulsant activity requires clarification. Other properties identified by basic research await evaluation. Standard treatments for many relevant disorders are unsatisfactory. Cannabis is safe in overdose but often produces unwanted effects, typically sedation, intoxication, clumsiness, dizziness, dry mouth, lowered blood pressure or increased heart rate. The discovery of specific receptors and natural ligands may lead to drug developments. Research is needed to optimise dose and route of administration, quantify therapeutic and adverse effects, and examine interactions.” (Robson, 2001)
Glass:
“An understanding of the actions of Cannabis (Marijuana) has evolved from folklore to science over the previous hundred years. This progression was spurred by the discovery of an endogenous cannabinoid system consisting of two receptors and two endogenous ligands. This system appears to be intricately involved in normal physiology, specifically in the control of movement, formation of memories and appetite control. As we are developing an increased understanding of the physiological role of endocannabinoids it is becoming clear that they may be involved in the pathology of several neurological diseases. Furthermore an array of potential therapeutic targets is being determined--including specific cannabinoid agonists and antagonists as well as compounds that interrupt the synthesis, uptake or metabolism of the endocannabinoids. This article reviews the recent progress in understanding the contribution of endocannabinoids to the pathology and therapy of Huntington's disease. Parkinson's disease, schizophrenia and tremor.” (Glass, 2001)
Porter:
“The active principle in marijuana, Delta(9)-tetrahydrocannabinol (THC), has been shown to have wide therapeutic application for a number of important medical conditions, including pain, anxiety, glaucoma, nausea, emesis, muscle spasms, and wasting diseases. Delta(9)-THC binds to and activates two known cannabinoid receptors found in mammalian tissue, CB1 and CB2. The development of cannabinoid-based therapeutics has focused predominantly on the CB1 receptor, based on its predominant and abundant localization in the CNS. Like most of the known cannabinoid agonists, Delta(9)-THC is lipophilic and relatively nonselective for both receptor subtypes. Clinical studies show that nonselective cannabinoid agonists are relatively safe and provide therapeutic efficacy, but that they also induce psychotropic side effects. Recent studies of the biosynthesis, release, transport, and disposition of anandamide are beginning to provide an understanding of the role of lipid transmitters in the CNS. This review attempts to link current understanding of the basic biology of the endocannabinoid nervous system to novel opportunities for therapeutic intervention. This new knowledge may facilitate the development of cannabinoid receptor-targeted therapeutics with improved safety and efficacy profiles.” (Porter, 2001)
The above summaries provide overwhelming acceptance by the scientific and medical community that cannabis and single cannabinoids can offer therapeutic benefits in many conditions, at least for some of the patients. Recent research on the mechanisms of action of THC and other ligands of the cannabinoid receptor improves the understanding of these benefits and lends further support to this finding.
References
Abrahamov A, Abrahamov A, Mechoulam R. An efficient new cannabinoid antiemetic in pediatric oncology. Life Sci 1995; 56(23-24): 2097-102
Beal JE, Olson R, Laubenstein L, Morales JO, Bellman P, Yangco B, Lefkowitz L, Plasse TF, Shepard KV. Dronabinol as a treatment for anorexia associated with weight loss in patients with AIDS. J Pain Symptom Manage 1995;10(2):89-97.
Beal JE, Olson R, Lefkowitz L, Laubenstein L, Bellman P, Yangco B, Morales JO, Murphy R, Powderly W, Plasse TF, Mosdell KW, Shepard KV. Long-term efficacy and safety of dronabinol for acquired immunodeficiency syndrome-associated anorexia. J Pain Symptom Manage 1997; 14(1): 7-14
Brenneisen R, Egli A, Elsohly MA, Henn V, Spiess Y. The effect of orally and rectally administered delta 9-tetrahydrocannabinol on spasticity: a pilot study with 2 patients. Int J Clin Pharmacol Ther 1996; 34(10): 446-52
British Medical Association. Therapeutic uses of cannabis. Amsterdam: Harwood Academic Publishers, 1997.
Calignano A, Katona I, Desarnaud F, Giuffrida A, La Rana G, Mackie K, Freund TF, Piomelli D. Bidirectional control of airway responsiveness by endogenous cannabinoids. Nature 2000; 408(6808): 96-101
Clifford DB. Tetrahydrocannabinol for tremor in multiple sclerosis. Ann Neurol 1983; 13(6): 669-71
Crawford WJ, Merritt JC. Effects of tetrahydrocannabinol on arterial and intraocular hypertension. Int J Clin Pharmacol Biopharm 1979; 17(5): 191-6
Dansak DA. As an antiemetic and appetite stimulant in cancer patients. In: Mathre ML, editor. Cannabis in medical practice: A legal, historical and pharmacological overview of the therapeutic use of marijuana. Jefferson/NC: McFarland & Co, 1997: 69-83
Elsner F, Radbruch L, Sabatowski R. Tetrahydrocannabinol zur Therapie chronischer Schmerzen [Tetrahydrocannabinol for treatment of chronic pain]. Schmerz 2001; 15(3): 200-4.
Gilson I, Busalacchi M. Marijuana for intractable hiccups. Lancet 1998; 351(9098): 267
Glass M. The role of cannabinoids in neurodegenerative diseases. Prog Neuropsychopharmacol Biol Psychiatry 2001;25(4):743-65.
Gordon E, Devinsky O. Alcohol and marijuana: effects on epilepsy and use by patients with epilepsy. Epilepsia 2001; 42(10): 1266-72.
Grinspoon L, Bakalar JB. Marihuana, the forbidden medicine. New Haven: Yale University Press, 1993
Grinspoon L, Bakalar JB. The use of cannabis as a mood stabilizer in bipolar disorder: anecdotal evidence and the need for clinical research. J Psychoactive Drugs 1998: 30(2): 171-7
Grotenhermen F, Russo E, editors. Cannabis and cannabinoids. Pharmacology, toxicology, and therapeutic potential. Binghamton NY: Haworth Press, 2002a.
Grotenhermen F. Pharmacokinetics and pharmacodynamics of cannabinoids. Clin Pharmacokin, 2002, in press.
Grotenhermen F. Review of therapeutic effects. In: Grotenhermen F, Russo E, editors. Cannabis and cannabinoids. Pharmacology, toxicology, and therapeutic potential. Binghamton NY: Haworth Press, 2002b: 123-42
Guzman M, Sanchez C, Galve-Roperh I. Control of the cell survival/death decision by cannabinoids. J Mol Med 2001; 78(11): 613-25
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
Hartley JP, Nogrady SG, Seaton A. Bronchodilator effect of delta1-tetrahydrocannabinol. Br J Clin Pharmacol 1978; 5(6): 523-5
Hemming M, Yellowlees PM. Effective treatment of Tourette's syndrome with marijuana. J Psychopharmacol 1993; 7: 389-91.
Hepler RS, Frank IR. Marihuana smoking and intraocular pressure. JAMA 1971; 217(10): 1392
Hepler RS, Petrus RJ. Experiences with administration of marihuana to glaucoma patients. In: Cohen S, Stillman RC, editors. The therapeutic potential of marihuana. New York: Plenum Medical Book, 1976: 63-75
Hollister L. Marijuana (cannabis) as medicine. J Cannabis Ther 2001;1(1):5-27.
House of Lords Select Committee on Science and Technology. Cannabis. The scientific and medical evidence. London: The Stationery Office, 1998
Izzo AA, Pinto L, Borrelli F, Capasso R, Mascolo N, Capasso F. Central and peripheral cannabinoid modulation of gastrointestinal transit in physiological states or during the diarrhoea induced by croton oil. Br J Pharmacol 2000; 129(8): 1627-32
Jacobsson SO, Wallin T, Fowler CJ. Inhibition of rat C6 glioma cell proliferation by endogenous and synthetic cannabinoids. Relative involvement of cannabinoid and vanilloid receptors. J Pharmacol Exp Ther 2001; 299(3): 951-9
Joy JE, Watson SJ, Benson JA, editors. Marijuana and medicine: Assessing the science base. Washington DC: Institute of Medicine, National Academy Press, 1999
Lane M, Vogel CL, Ferguson J, Krasnow S, Saiers JL, Hamm J, Salva K, Wiernik PH, Holroyde CP, Hammill S, et al. Dronabinol and prochlorperazine in combination for treatment of cancer chemotherapy-induced nausea and vomiting. J Pain Symptom Manage 1991; 6(6): 352-9
Mathre ML, editor. Cannabis in medical practice: A legal, historical and pharmacological overview of the therapeutic use of marijuana. Jefferson, NC: McFarland & Co, 1997
Maurer M, Henn V, Dittrich A, Hofmann A. Delta-9-tetrahydrocannabinol shows antispastic and analgesic effects in a single case double-blind trial. Eur Arch Psychiatry Neurol Sci 1990; 240(1): 1-4
Mechoulam R, editor. Cannabinoids as therapeutic agents. Boca Raton: CRC Press, 1986
Mechoulam R, Shohami E. HU-211: Cannabinoid Neuroprotective Agent. In: Grotenhermen F, Russo E, editors. Cannabis and cannabinoids. Pharmacology, toxicology, and therapeutic potential. Binghamton (NY): Haworth Press, 2002: 389-400
Meinck HM, Schonle PW, Conrad B. Effect of cannabinoids on spasticity and ataxia in multiple sclerosis. J Neurol 1989; 236(2): 120-2
Melamede R. Possible mechanisms in autoimmune diseases. In: Grotenhermen F, Russo E, editors. Cannabis and cannabinoids. Pharmacology, toxicology, and therapeutic potential. Binghamton (NY): Haworth Press, 2002: 111-122
Merritt JC, Crawford WJ, Alexander PC, Anduze AL, Gelbart SS. Effect of marihuana on intraocular and blood pressure in glaucoma. Ophthalmology 1980; 87(3): 222-8
Merritt JC, Olsen JL, Armstrong JR, McKinnon SM. Topical delta 9-tetrahydrocannabinol in hypertensive glaucomas. J Pharm Pharmacol 1981; 33(1): 40-1
Mikuriya TH. Cannabis substitution. An adjunctive therapeutic tool in the treatment of alcoholism. Med Times 1970; 98(4): 187-91
Mueller-Vahl KR, Kolbe H, Schneider U, Emrich HM. Movement Disorders. In: Grotenhermen F, Russo E, editors. Cannabis and cannabinoids. Pharmacology, toxicology, and therapeutic potential. Binghamton (NY): Haworth Press, 2002: 205-214
Mueller-Vahl KR, Schneider U, Kolbe H, Emrich HM. Treatment of Tourette's syndrome with delta-9-tetrahydrocannabinol. Am J Psychiatry 1999; 156(3): 495
Notcutt W, Price M, Miller R, Newport S, Sansom C, Simmonds S. Medicinal cannabis extracts in chronic pain: (2) comparison of two patients with back pain and sciatica. 2001 Congress on Cannabis and the Cannabinoids, Cologne, Germany: International Aaasociation for Cannabis as Medicine, p. 25
Notcutt W, Price M, Miller R, Newport S, Sansom C, Simmonds S. Medicinal cannabis extracts in chronic pain: (3) comparison of two patients with multiple sclerosis. 2001 Congress on Cannabis and the Cannabinoids, Cologne, Germany: International Aaasociation for Cannabis as Medicine, p. 26
Noyes R Jr, Brunk SF, Avery DAH, Canter AC. The analgesic properties of delta-9-tetrahydrocannabinol and codeine. Clin Pharmacol Ther 1975a; 18(1): 84-9
Noyes R Jr, Brunk SF, Baram DA, Canter A. Analgesic effect of delta-9-tetrahydrocannabinol. J Clin Pharmacol 1975b; 15(2-3): 139-43
Petro DJ, Ellenberger C Jr. Treatment of human spasticity with delta 9-tetrahydrocannabinol. J Clin Pharmacol 1981; 21(8-9 Suppl): 413S-6S
Petro DJ. Marihuana as a therapeutic agent for muscle spasm or spasticity. Psychosomatics 1980; 21(1): 81, 85
Plasse TF, Gorter RW, Krasnow SH, Lane M, Shepard KV, Wadleigh RG. Recent clinical experience with dronabinol. Pharmacol Biochem Behav 1991; 40(3): 695-700
Porter AC, Felder CC. The endocannabinoid nervous system: unique opportunities for therapeutic intervention. Pharmacol Ther 2001;90(1):45-60.
Ralevic V, Kendall DA. Cannabinoid inhibition of capsaicin-sensitive sensory neurotransmission in the rat mesenteric arterial bed. Eur J Pharmacol 2001; 418(1-2): 117-25
Robson P. Therapeutic aspects of cannabis and cannabinoids. Br J Psychiatry 2001;178:107-15.
Sallan SE, Cronin C, Zelen M, Zinberg NE. Antiemetics in patients receiving chemotherapy for cancer: a randomized comparison of delta-9-tetrahydrocannabinol and prochlorperazine. N Engl J Med 1980; 302(3): 135-8
Sanchez C, de Ceballos ML, del Pulgar TG, Rueda D, Corbacho C, Velasco G, Galve-Roperh I, Huffman JW, Ramon y Cajal S, Guzman M. Inhibition of glioma growth in vivo by selective activation of the CB(2) cannabinoid receptor. Cancer Res 2001; 61(15): 5784-9
Sandyk R, Awerbuch G. Marijuana and Tourette's syndrome. J Clin Psychopharmacol 1998; 8: 844
Schnelle M, Grotenhermen F, Reif M, Gorter RW. Ergebnisse einer standardisierten Umfrage zur medizinischen Verwendung von Cannabisprodukten im deutschen Sprachraum, [Results of a standardized survey on the medical use of cannabis products in the German-speaking area]. 1999; (Suppl 3) 28-36. Forsch Komplementarmed [Res Complementary Med] 1999; (Suppl 3) 28-36
Sieradzan KA, Fox SH, Hill M, Dick JP, Crossman AR, Brotchie JM. Cannabinoids reduce levodopa-induced dyskinesia in Parkinson's disease: a pilot study. Neurology 2001; 57(11): 2108-11.
Tashkin DP, Shapiro BJ, Frank IM. Acute effects of smoked marijuana and oral ?9-tetrahydrocannabinol on specific airway conductance in asthmatic subjects. Am Rev Respir Dis 1974; 109(4): 420-8
Ungerleider JT, Andyrsiak T, Fairbanks L, Ellison GW, Myers LW. Delta-9-THC in the treatment of spasticity associated with multiple sclerosis. Adv Alcohol Subst Abuse 1987; 7(1): 39-50
Volicer L, Stelly M, Morris J, McLaughlin J, Volicer BJ. Effects of dronabinol on anorexia and disturbed behavior in patients with Alzheimer's disease. Int J Geriatr Psychiatry 1997; 12(9): 913-9
Wagner JA, Jarai Z, Batkai S, Kunos G. Hemodynamic effects of cannabinoids: coronary and cerebral vasodilation mediated by cannabinoid CB(1) receptors. Eur J Pharmacol 2001; 423(2-3): 203-10
Williams SJ, Hartley JP, Graham JD. Bronchodilator effect of delta1-tetrahydrocannabinol administered by aerosol of asthmatic patients. Thorax 1976; 31(6): 720-3
Williamson EM, Evans FJ. Cannabinoids in clinical practice. Drugs 2000;60(6):1303-14.
