Source: Patient Care, v32 n2 p41(6). Author: Prepared By Lori D. Talarico, Senior Associate Editor Author: Lisa Capaldina, Donald Tashkin, William Vilensky and Lori D. Talarico Pubdate: Jan 30, 1998 Editors note: Couldn't find a contact on the web, and this is a little old, but could not pass it up. If anyone has contact info for this magazine please drop me a note. Oh, I did find the following good list of 400 some medical journals with online pages: http://canada.silverplatter.com/physicians/library/journlst.htm It is also nice that Patient Care recommends reading sections of the DrugLibrary at: http://www.druglibrary.org/ DOES MARIJUANA HAVE A PLACE IN MEDICINE? Abstract: Few studies have been conducted on the medical efficacy of smoked marijuana although substantial anecdotal evidence suggests smoked marijuana has many therapeutic uses such as the ability to enhance the appetite in AIDS patients and control nausea and vomiting due to cancer chemotherapy. In the moral, legal, and medical realms, the use of medical marijuana is a hotly contested issue. What do we really know about its efficacy? When, if ever, is it recommended? In the crude herb Cannabis sativa L. (Cannabaceae)--more commonly known as marijuana, pot, or hemp--delta-9-tetrahydrocannabinol (THC) occurs as a sticky, extractable, resinous oil. In total, marijuana contains more than 60 cannabinoids, most of them poorly characterized. The major psychoactive ingredient appears to be THC, however. Whether marijuana is smoked, eaten, brewed in a tea, or swallowed in pill form, THC is the major ingredient affecting the CNS. This is also true of dronabinol, marijuana's chemically synthesized THC counterpart ("medical marijuana"), which is formulated in sesame oil and supplied in 2.5-, 5-, or 10-mg gelatin capsules. Some argue that manufacturing dronabinol by extracting only one of many cannabinoids produces an agent that is less effective than the polypharmaceutical herb marijuana.[1] Others feel very strongly that as long as dronabinol is available, the Drug Enforcement Agency (DEA) does not need to reschedule crude marijuana as a medicinal drug. With the passage of bills in California and Arizona recognizing marijuana as a medication, there is increasing political and public pressure for a final decision on the legal status of smoked marijuana as a regulated substance prescribed for medicinal purposes. The few studies that have examined the medical efficacy of smoked marijuana were conducted in the 1970s and 1980s. While the debate rages, marijuana remains illegal, and dronabinol is the only legally available THC. With the advent of serotonin antagonists, the need for medicinal THC as an antiemetic is less clear than ever. HOW DRONABINOL WORKS Dronabinol, a Schedule II (prescription only) controlled substance, affects receptors in the brain and the spinal cord. It is labeled for use in the treatment of anorexia associated with weight loss in patients with AIDS and for the nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to conventional antiemetic treatment. Although it is an efficacious antiemetic, it may have significant side effects.[2] Dronabinol is often used as a rescue medication when other drugs do not work, rather than as a first-line treatment. It is prescribed primarily by oncologists, although other physicians use it off-label, either alone or as an adjunct, in treating glaucoma and epilepsy and to relieve tremor, ataxia, and muscular spasticity in patients with multiple sclerosis (MS). Dronabinol is clearly most useful as a treatment option when nausea and vomiting are uncontrolled by other means, and its stimulating effect on the appetite may continue for 24 hours or longer after administration. It can also be administered with a variety of medications (eg, many cytotoxic agents, anti-infective agents, sedatives, or opioid analgesics) without causing clinically significant drug interactions. Synthetic THC may interact with some medications, however, through both metabolic and pharmacodynamic mechanisms, at least theoretically. Dronabinol is highly protein-bound, for example, and therefore might displace other protein-bound drugs, and patients should be monitored for possible changes in dosage requirements. Oral THC capsules have other disadvantages. A patient suffering from nausea and vomiting may be unable to swallow the pill or keep it down. A suppository form appears to have been successful in clinical trials, but it is not yet available. Trials with a dronabinol nasal inhaler are also under way. It is difficult to titrate dronabinol because of its erratic bioavailability and relatively slow onset of action. Onset is delayed for approximately 30-60 minutes, with a peak effect at 2-4 hours. The psychoactive effects last for 4-6 hours, and side effects may be prolonged. Dronabinol-induced parasympatholytic-like activity may result in tachycardia or conjunctivitis. Effects on blood pressure are inconsistent, and some patients have experienced orthostatic hypotension or syncope. Dronabinol must be taken on a regular schedule; treatment is initiated with a low dosage (2.5 mg/d), which is increased only as necessary. Possible psychoactive side effects include impairment of coordination, mood, and perception and are the biggest drawback to the medical use of THC. They may be most severe in patients who are not experienced cannabinoid users. Tachyphylaxis and tolerance to some of the pharmacological effects develop with chronic use. ALTERNATIVES TO THC At least seven controlled studies comparing prochlorperazine maleate with synthetic THC were performed more than a decade ago.[3] Several other antiemetics have come to the fore since then, but they have not been compared to THC in controlled clinical trials. These newer drugs include the serotonin antagonists ondansetron HCl dihydrate and granisetron HCl, which are more effective and cause fewer side effects than prochlorperazine and can be administered to children. A number of dopamine receptor blockers are currently used to treat nausea, including metoclopramide HCl, haloperidol, and cisapride. Two studies comparing the antiemetic effects of oral THC and metoclopramide have yielded mixed results.[3, 4] Corticosteroids like dexamethasone and methylprednisolone acetate and minor tranquilizers, such as lorazepam, have proven safe and effective for the treatment of chemotherapy-induced nausea and vomiting, especially when used in conjunction with other antinausea medications such as scopolamine.[5] Even a combination sedative/antiemetic in the phenothiazine family, such as chlorpromazine HCl, can be used. INHALED MARIJUANA Few of the more than 60 active cannabinoids found in crude marijuana have been studied. There is speculation that some of the non-THC cannabinoids may help confer the additional benefits reported by those who smoke or eat marijuana, although no human trials confirm this. Little information about the efficacy of inhaled marijuana has been derived from clinical trials, but an abundance of anecdotal and clinical reports exist. In fact, marijuana was widely prescribed by Western physicians in the mid-19th century for asthma, insomnia, dysmenorrhea, convulsions, and a number of other complaints. Today, whole cannabis is thought to be effective in a wide range of conditions, including appetite enhancement for the wasting syndrome of AIDS, control of nausea and vomiting associated with cancer chemotherapy, relief of spasticity and pain associated with MS, a decrease in intraocular pressure in glaucoma, and control of migraine headaches and epileptic seizures. Many of the compounds contained in marijuana have demonstrated pain-relieving actions in animal tests, although few studies of cannabinoid effects on pain have been conducted in humans.[6] As is the case with dronabinol, these benefits come with possible psychotropic effects that can impair normal activities. Inhaling smoke, which irritates the throat and lungs, can lead to respiratory problems. Marijuana use by patients with AIDS is discouraged since it is not known to what extent marijuana may further compromise the lungs' immune defenses and predispose the patient to opportunistic pulmonary infections.[7, 8] The illegality of marijuana has made it difficult to scientifically document a connection with lung disease or the effects of passive exposure to marijuana smoke. It has been suggested that alternate drug delivery devices and marijuana extracts be studied for use in lieu of smoking an unfiltered marijuana cigarette. Examples include different kinds of water pipes, filters, and vaporizing devices that could selectively remove potentially harmful elements from marijuana smoke. Water pipes have always been available as illegal drug paraphernalia. Research has shown that THC, the active antinausea agent in marijuana, is more quickly absorbed when marijuana is smoked rather than ingested. According to one study, a substantial proportion of practicing oncologists who responded to the survey regard smoked cannabis as a safe and effective antinausea agent.[1] COMPARING DRONABINOL AND MARIJUANA Quality control is another factor to consider when comparing dronabinol with smoked marijuana. The synthetic THC found in dronabinol is manufactured under sterile, controlled conditions. There are numerous variables in the production of illegal marijuana. The quality of the herb is affected by soil conditions, water quality, and humidity and temperature control. For example, like all plants, cannabis accumulates metal from the soil, and soils in different parts of the country contain varying levels of mercury, lithium, cadmium, and copper. Since the crop is produced illegally, contamination by unrestricted use or overuse of pesticides, herbicides, fungicides, or insecticides may occur. In addition, the marijuana plant is often plagued with pathogenic fungi, such as Aspergillus or Fusarium. It can also transmit other fungal infections such as histoplasmosis. This problem can be eradicated by proper sterilization, though, and baking marijuana kills Aspergillus spores with no effect on THC content.[9] Dronabinol can be produced in specific potencies, but variations in growing climate and product preparation greatly affect available THC levels in marijuana. The more potent, resinous hemp is grown in hot, moist southern climates. Furthermore, the concentration of THC in a marijuana cigarette, commonly called a joint, which contains dried stems, leaves, and flowers, is much lower than the THC level in hashish--a preparation of the unadulterated resin scraped from the flowering tops of the female hemp plants. Hashish, or hash, is usually shaped like a bar of soap, and a piece is broken off and used in a pipe or water pipe, or sometimes crumbled up with marijuana and rolled into a cigarette. Like marijuana, it can be eaten. Government-produced cigarettes sponsored by the National Institute on Drug Abuse are reported to be bacteria- and fungus-free as well as consistent in THC level. Many supporters of marijuana for medical use, therefore, support governmental control of the production of cannabis for safety and consistency of THC levels and the elimination of fungi and bacteria. The bioavailability of dronabinol and marijuana vary tremendously in individuals and from day to day in the same person. Even though synthetic THC is available in three strengths, it can be very difficult to define appropriate dose and determine what time day the patient needs to take it. Some stud suggest that smoking is a more efficient delivery system for THC than dronabinol because the patient gets near-immediate results and can self-titrate--although the ability to self-titrate has been questioned.[10] Smoking marijuana appears to surpass eating crude marijuana in terms of control of titration. In addition, eating marijuana may be difficult for patients who are anorectic, nauseated, or vomiting.[10, 11] Smoking a cannabis cigarette is associated with a nearly fivefold increase in the carboxyhemoglobin concentration compared to that associated with smoking a tobacco cigarette. More tar is also inhaled and retained in the respiratory tract when smoking marijuana.[12] It's true too, however, that the medicinal use of inhaled marijuana entails smoking far fewer cigarettes than the number typically smoked by a tobacco user. Cardiac effects such as tachycardia and hypotension are common with both dronabinol and smoked marijuana. Although these effects may be of minimal consequence in younger persons, elderly patients may be more sensitive to them. The adverse reactions can also be more prominent in the inexperienced marijuana user. Proponents of smoked marijuana for medical use believe that government-approved marijuana would be less expensive than dronabinol or the new antiemetics. For example, ondansetron costs $120-$160 for oral administration but, because of nausea and vomiting, especially in AIDS patients, IV administration is often required at a cost of about $600.[13] Without the black market, the price of government-grown marijuana cigarettes could be quite low. WHAT'S NEXT Supporters of smoked marijuana for medical use believe that governmental control over marijuana as a Schedule I substance (no currently accepted medical use) has prevented an objective evaluation of the drug in controlled clinical trials. In fact, no major trials to assess marijuana's safety or efficacy have been conducted. Some people believe that the federal government should remove legal barriers to research, provide direct or indirect financial support to research, and, in the meantime, allow continued and expanded use of the drug on a compassionate-use basis. [14, 15] Many physicians say that if cannabinoids are found to be as effective as other available medications, they would prescribe them. At the least, many physicians would like to put the issue to rest once and for all. Many doctors believe that the greatest danger in the medical use of marijuana is its illegality, which imposes much anxiety and expense on suffering people, forces them to bargain with illicit drug dealers, and exposes them to threats of criminal prosecution. Only clinical research comparing dronabinol to other tetrahydro-cannabinoids and cannabinoids for therapeutic efficacy can clarify this controversy. The National Institutes of Health are open to receiving research grant applications for studies of the medical efficacy of marijuana, and they have recently provided a $1 million grant to the Institute of Medicine to review scientific and laboratory tests on marijuana. RELATED ARTICLE: Drugs mentioned in this article Chlorpromazine HCI (Thorazine) Cisapride (Propulsid Dexamethasone (Decadron, Hexadrol) Granisetron HCI (Kytril) Haloperidol (Haldol) Lorazepam (Ativan) Methylprednisolone acetate (Deop-Medrol) Metoclopramide HCI (Zofran) Prochlorperazine maleate (Compazine) Scopolamine HBr (injectable) REFERENCES [1.] Doblin RE, Kleiman MAR: Marijuana as antiemetic medicine: A survey of oncologists' experiences and attitudes. J Clin Oncol 1991;9:1314-1319. [2.] Beal JE, Olson DO, Laubenstein L, et al: Dronabinol as a treatment for anorexia associated with weight loss in patients with AIDS. J Pain Sympton Manage 1995;10:89-97. [3.] Ekert H, Waters KD, Jurk IH, et al: Amerlioration of cancer chemotherapy-induced nausea and vomiting by delta-9-tetrahyrdocannabinol. Med J Aust 1979;2:657-659. [4.] Gralia RJ, Tyson LB, Clark RA, et al: Antiemetic trials with high dose metoclopramide: Superiority over THC, preservation of efficacy in subsequent chemotherapy courses, abstracted. Proceedings of the American Society of Clinical Oncology 1982;1:58. [5.] Grunberg SM, Hesketh PJ: Control of chemotherapy-induced emesis. N Engl J Med 1993;24:1790-1796. [6.] Hardman JG (ed): Goodman and Gilman's: The Pharmacological Basis of Therapeutics, Ninth Edition. New York, McGraw-Hill, 1996. [7.] Sherman MP, Campbell LA, Gong H Jr, et al: Antimicrobial and respiratory burst characteristics of pulmonary alveolar macrophages recovered from smokers of marijuana alone, smokers of tobacco alone, smokers of marijuana and tobacco, and nonsmokers. Am Rev Respir Dis 1991;144:1351-1356. [8.] Baldwin GC, Tashkin DP, Buckley DM, et al: Marijuana and cocaine impair alveolar macrophage function and cytokine production. Am J Respir Care Med 1997;156:1606-1613. [9.] Levitz SM, Diamond RD: Aspergillosis and marijuana. Ann Intern Med 1991; 115:578-579. [10.] Matthias P, Tashkin DP, Marques-Magallanes JA, et al: Effects of varying marijuana potency on deposition of tar and [Delta][9]-THC in the lung during smoking. Pharmacol Biochem Behav 1997;58:1045-1050. [11.] Mattes RD, Engelman K, Shaw LM, et al: Cannabinoids and appettite stimulation. Pharmacol Biochem Behav 1994;49:187-195. [12.] Nahas G, Latour C: The human toxicity of marijuana. Med J Aust 1992; 156:495-497. [13.] Nelan EH: Medical marijuana: Research priority, hoax or civil right? Gay Men's Health Crisis Treatment Issues 1997;11:1-3. [14.] Kassirer JP: Federal foolishness and marijuana, editorial, N Engl J Med 1997; 336-336-367. [15.] Annas GJ: Reefer madness: The federal response to California's medical-marijuana law. N Engl J Med 1997;337:435-439. SUGGESTED READING Grinspoon L, Bakalar JB: Maruhuana as medicine: a plea for reconsideration. http://206.61.184.43/schaffer/hemp/medical/grinjama/htm Grinspoon L, Bakalar J: Marihuana, the Forbidden Medicine, New Haven, Conn, Yale Univ Pr, 1993. Major studies of drugs and drug policy, http://206.61.184.43/schaffer/library/ studies/studies.com Report of the US National Commission of Marihuana and Drug Abuse, 1972: History of marijuana use: Medical and antoxicant. http://206.61.184.43/schaffer/ library/studies/nc/nc1a.htm Rosenthal E, Mikuriya T, Gieringer D: Marijuana Medical Handbook: A guide to therapeutic use. Oakland, Calif, Quick American Archives, 1997. Schwartz RH, Beveridge RA: Marijuana as an antiemetic drug: How useful is it today? Opinions from clinical oncologists. J Addict Dis 1994;13:53-65. Schwartz RH, voth EA, Sheridan MJ: Marijuana to prevent neusea and vomiting in cancer patients: A survey of clinical oncologists. South Med J 1997;90:167-172. Voth EA, Schwartz RH: Medicinal applications of delta-9-tetrahydrocannabinol and marijuana. Ann Intern Med 1997;126-791-798. Wu T-C, Tashkin DP, Djahed B, et al: Pulmonary hazards of smoking marijuana as compared with tobacco. N Engl J Med 1988;318:347-351. ARTICLE CONSULTANTS LISA CAPADINI, MD is Associate clinical Professor of Medicine, University of California, San Francisco, School of Medicine; and Director, Castro Medical Clinic, San Francisco. DONALD TASHKIN, MD, is Professor of Medicine, Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California, Los Angeles, UCLA School of Medicine; and a researcher for the National Institute on Drug Abuse, Bethesda, Md. WILLIAM VILENSKY, RPh, DO, is Clinical Associate Professor, Department of Family Medicine, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, Piscataway; Clinical Associate Professor, Department of Psychiatry. UMDMJ--New Jersey Medical School, Newark; and Executive Medical Director, Forensic and Educational Consultants, Margate, N.J. Full Text COPYRIGHT 1998 Medical Economics Publishing