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Daniel A. Dansak, M.D., is a practicing psychiatrist at the University of Southern Alabama in Mobile.
In 1977, a 26-year-old male cancer patient from New Mexico approached the states legislature with an astounding proposal: legalize marijuana for cancer patients. His reason: smoking marijuana reduced the nausea and vomiting side effects of the therapeutic drugs given by doctors to combat his metastatic cancer. Many other cancer patients could have the same benefit, he argued, except for the fact that marijuana was illegal to purchase or possess. Apparently legal antiemetic drugs were not very effective for the severe symptoms of nausea and vomiting that cancer patients suffered. Some patients even chose to stop anticancer chemotherapy because of the discomfort. And worse, because they stopped treatment, some patients died. This young cancer patient named Lynn Pierson also knew of other cancer patients around the United States who had used or were using marijuana to control the nausea and vomiting side effects of anti-cancer drugs.
One sympathetic New Mexican legislator, Tom Rutherford, sent Lynn Pierson's request on for further research. The Legislative Counsel Office then approached the University of New Mexico's Cancer Research and Treatment Center for assistance. A review of the scientific literature produced a number of reports by reputable investigators in high-quality journals attesting to the effectiveness of cannabis in reducing the nausea and vomiting side effects of anticancer medications. The most notable report was that of Dr. Steven Sallan and his group at Massachusetts General Hospital in Boston, a teaching hospital associated with Harvard University's Medical School (Sallan et al. 1975).
Based on the available evidence, the state legislature of New Mexico subsequently passed a law allowing cancer patients to use cannabis to control the nausea and emetic side effects caused by their treatment. However, because federal laws under the Food and Drug Administration (FDA) and Drug Enforcement Administration (DEA) also applied, the legislature required that marijuana or its psychoactive chemical (delta-9-THC) be given to cancer patients only under the auspices of a research program that would meet the scientific and legal requirements of the above two federal agencies and any others with similar authority. The National Institute of Drug Abuse (NIDA) and the National Cancer Institute (NCI) were two such additional agencies. The intent of the state legislature was to get marijuana or delta-9- THC to cancer patients in New Mexico who wanted and needed it. Federal agencies, however, wanted reasonable, scientific information to help in making decisions about the drug. Both intentions were equally important.
Many scientists in New Mexico and elsewhere were initially interested in conducting research on the effects of marijuana and delta-9-THC on nausea and vomiting in cancer patients. Their interest gradually disappeared as it became clear that neither the state of New Mexico nor the federal government would provide funds to start or run any program. However, a few concerned individuals at the New Mexico Cancer Control Program,,a federally funded community cancer education and training program, found that such a research and service program would mesh extremely well with the program's other missions. A research protocol was prepared and submitted through the University of New Mexico to the FDA, DEA, NCI, and NIDA. After many months of review and refinement, and with much encouragement and assistance from federal and state scientists and administrators, the protocol was approved. Nearly one year after New Mexico passed the law allowing marijuana for cancer patients, medication supplies arrived and were dispensed under this protocol to those who wanted and needed them. Regrettably, Lynn Pierson, who had started the entire process, was not one of the recipients. He had died of cancer several months before the program began. Once begun, the research program attracted a steady flow of patients from all over the state of New Mexico. Eventually, the state of New Mexico funded the project and renamed it the Lynn Pierson Therapeutic Research Program. Five other states (Georgia, Michigan, New York, Tennessee and California) conducted similar studies in the late 1970s to mid-1980s, all concluding marijuana was an effective antiemetic (Randall 1989, 36-54).
Background: Adverse Effects of Chemotherapy
Many of the chemotherapeutic drugs used to treat cancer are highly lethal agents with intense and potentially overwhelming side effects. The goal of chemotherapy is to kill cancer cells. However, the chemotherapeutic agent cannot differentiate between cancer cells and healthy cells and destroys the latter as well. In addition, devastating side effects can also result depending on the type of chemotherapy administered. Some commonly used chemotherapy drugs are so strong that some individuals vomit for hours or days, followed by days or weeks of nausea. This nausea prevents eating, and many chemotherapy patients cannot tolerate the sight or smell of cooked foods. In addition, a metallic taste often develops after treatment. The inability to eat, or to retain food once it is eaten, can obviously result in drastic weight loss. And as weight is lost, strength is lost as well, and the individual becomes less and less able to cope with the disease and treatment. In some individuals, anticipatory nausea and vomiting begins. One patient reported feeling nauseated from merely driving past the doctor's office. Upon seeing the chemotherapy nurse at the grocery store, another patient reported being so nauseated that he had to leave the store. These episodes of nausea are conditioned responses due to associations with past treatment experiences. In fact, anything that reminds the patient of a negative chemotherapy experience may trigger nausea and vomiting (Redd 1984).
The response to repeated episodes of chemotherapy compromises the already stressed system with further weight loss, nutritional deficit, and dehydration. Resultant psychological problems can include dread of the next treatment and later depression. The individual's sense of control over his or her life is lost. Consequently, not only does the individual have to deal with cancer, he,or she also has to deal with the side effects of treatment. Given this, the individual may ultimately give up. For a person with cancer undergoing chemotherapy or radiation therapy there is probably nothing worse (except uncontrollable pain) than the added stress of loss of control related to nausea and vomiting.
Study Description
The Lynn Pierson Therapeutic Research Program allowed selected cancer patients to smoke natural cannabis, in standard-dose cigarette form, or take pills containing the psychoactive ingredient of cannabis, delta-9-THC. To participate in the cannabis program, individuals had to meet several criteria. First, the cancer patient was required to initially try at least one conventional antiemetic drug, such as Reglan, Torecan, or Compazine. If one of these drugs was effective and there were no side effects, the individual was not accepted for participation in the marijuana study. Second, it was required that the treating physician be fully informed of the individual's desire to participate and agree to allow him to do so. All oncologists in New Mexico were informed about the program, and a majority of them referred patients. And finally, patients could not be so physically ill that the drug, smoked or swallowed, would cause significant side effects or worsen the patient's condition. Cannabis, like many legal drugs and all illegal drugs, has psychological effects. Therefore, patients also had to be screened for mental disorders that might be affected by its use. After successfully clearing these medical and psychiatric hurdles (fewer than 10 patients of more than 220 who applied did not participate), patients were arbitrarily assigned to receive either oral or smoked cannabis.
Patients who refused to or could not smoke (about ten people) were given oral medication. All patients received their medication under controlled conditions at the same time they were receiving their anticancer chemotherapy. A cannabis cigarette was smoked immediately before or the capsules were swallowed about 30 minutes prior to anticancer treatment. For the next four hours following ingestion of cannabis or delta-9-THC, the patients were closely watched by a nurse or physician. Blood pressure, pulse rate, psychological condition, and known side effects were monitored periodically. Each patient also rated the intensity of nausea, vomiting, and appetite problems experienced. In addition, a few patients gave blood samples at specified intervals during the four-hour observation period so that levels of delta-9-THC and its metabolite could be measured. If no significant problems occurred, patients could then take the medication home to be used as prescribed for the next two to five days, the usual duration. To assure the safety of the patients and effectiveness of the medication, telephone contact was maintained with patients or family during this period as well.
Patients who decided to continue using either form of medication after this initial dosing were then seen at each subsequent chemotherapy treatment. Their medical and psychiatric status was briefly evaluated to assure continued need for the medication and to assess any changes that may have occurred and could interfere with or be worsened by marijuana. Sometimes chemotherapy was changed to types that did not induce nausea or vomiting. At such times, patients were not given additional cannabis or delta-9-THC. In other situations, the cancer progressed so rapidly that it produced physical changes that would interfere with the use of one form of the drug or both. Patients could then be switched or discontinued as appropriate. Although patients were followed closely after the initial dosing, subsequent dosings did not require the close, four-hour observation and monitoring described above.
It must be emphasized that all patients chose to participate in this study.
A standard research-informed consent was read and signed by the patient. If a patient was under the age of 18, special permission from the Human
Research Review Committee (HRRC) was obtained. There was no payment or other incentive for them beyond the hope of reducing or alleviating their discomfort. There was also no charge to the patients for the cannabis or THC capsules, and patients could drop out at any time, for any reason, without any penalty. And, as I have described above in some detail, patients were evaluated closely and regularly for their safety and comfort. The patients always knew what drug they were getting, and there was no use of placebos or ineffective agents in this study.
From 1979 to 1986 approximately 256 women and men, ages 18 to 77, from all walks of life, participated in the Lynn Pierson Therapeutic Research and Treatment Program at the University of New Mexico. These individuals, from 46 communities in New Mexico, suffered from 22 different types of cancer and had a combined experience of over 2,000 episodes of chemotherapy-induced nausea and vomiting, lasting one day to several weeks per episode. Not all individuals experienced the same intensity of response to particular types of chemotherapy; however, for some people with cancer, it is easy to understand why treatment sometimes feels worse than the disease itself.
One of the major difficulties in a study like this is to find a reasonably accurate baseline measure of nausea and vomiting to compare against the effectiveness of cannabis or delta-9-THC. This was done by asking patients at the time they were applying for admission to the study to rate the severity of their nausea, vomiting, and appetite problems at their most recent chemotherapy session. All patients also received some form of conventional antiemetic during that session so the effect of cannabis or delta-9-THC as an antiemetic or appetite stimulant could be compared with standard treatments.
The main reason for not using those measures of symptoms taken immediately prior to chemotherapy administration was the problem of anticipatory nausea and vomiting. It was well known then that many patients began experiencing nausea, vomiting and appetite problems hours before ever receiving anticancer drugs, in anticipation or expectation of such side effects. In summary, the comparison points were: chemotherapy plus conventional anti-emetics versus chemotherapy plus cannabis or delta-9-Mc.
Because patients may not accurately recall what happened at their most recent chemotherapy treatment, patients had to rate their past nausea and vomiting twice. They made an assessment at the time of applying to the program and again just before receiving cannabis and chemotherapy. Data was available for 74 patients at these two times and showed no statistical difference in the mean ratings. The median time between the two ratings was 11 days (range 1 to 150 days).
Knowledgeable or experienced readers may well be aware that physicians change chemotherapy for cancer patients. Sometimes they switch from drugs that produce little or no side effects to ones that produce severe nausea and vomiting, or vice versa. Thus, one additional factor that had to be considered was that patients received the same type of chemotherapy at the two treatment sessions. That is, a patient, who had severe nausea and vomiting from a most recent treatment session, would again receive chemotherapy expected to produce severe nausea and vomiting for the session during which the cannabis would be given.
In this regard the scientific literature was reviewed to classify chemotherapy agents and doses as mild, moderate, and severe, depending on the severity of nausea and vomiting induced. Then, physician oncologists (specialists in cancer treatment) and oncology nurses (specialists in cancer patient care) were asked to rate the same chemotherapy agents and doses as mild, moderate, or severe emetics. They had no idea about the investigating team's rating and thus were only reporting their own knowledge and experience. Using a statistical procedure called correlation, moderate to high correlations were found among the ratings, indicating the earlier classification was reasonably accurate (Table 1).
*This is a very general classification. There is wide variation among patients in frequency, severity, and duration of nausea and vomiting. Moreover, many patients receive combinations of agents which further complicates any rigid classification.
A number of new antiemetics have come on the market the past few years, agents that were not available during the time of this study with cancer patients. The first of these was ondansetron (Zofran). It is effective in reducing or blocking nausea and vomiting in 80 percent of patients, but it is associated with headaches, constipation, and or abdominal pain in 4 percent to 23 percent of patients. The cost per tablet is quite variable but can be $45.00. At three 8 mg tablets per day for two days, the total cost may be $270.00. Granesetron (Kytril) is a related antiemetic effective in reducing nausea and vomiting in 60 percent to 90 percent of patients. Headache, constipation, and or weakness are the most common side effects, occurring in 14 percent to 21 percent of patients. For two 1 mg tablets given daily for a two-day chemotherapy treatment the total cost can be $380.00.
Dronabinol (Marinol), the synthetic oral form of the active ingredient of marijuana (delta-9-tetrahydrocannabinol) is given four to six times per day to control nausea and vomiting. The common side effects are drowsiness, dizziness, euphoria, and abdominal pain in 3 percent to 10 percent of patients. The cost for two days of chemotherapy is about $90.00 to $138.00.
A combination treatment sometimes used is metachlopromide and depamethasome. This may be effective in 60 percent of patients but has side effects of mood changes, drowsiness, and possibly hallucinations or bizarre thinking. The cost of this treatment is lowest, perhaps $2.00 to $3.00 for a two-day chemotherapy treatment, but it has limited effectiveness and the side effects Are considered extreme.
Results: Nausea and Vomiting
Although many more patients participated in the study, data analysis was done for 169 patients. Using the comparison points noted above and having ascertained that 92 percent of the patients received the same or worse chemotherapy in the experimental session, it was found that both nausea and vomiting average scores were reduced by half with the use of cannabis (Table 2). In scientific terms, this was a "statistically significant" result. Mild, moderate, and severe chemotherapy classes were looked at next. Patients on chemotherapy drugs causing mild or moderate nausea and vomiting improved by about 60 percent, while those on severe agents had a 40 percent reduction in symptoms. The latter, though less, was still "statistically significant" (Table 3). Given the evidence already existing in the scientific literature, this result was not unexpected.
1 = not a problem; 2 = slight; 3 = mild; 4 = moderate; 5 = severe
A central question for this study concerned the effectiveness of oral versus inhaled forms of medication. People who smoked had a greater than 50 percent reduction in nausea and vomiting, while those who took the pills had slightly less than a 50 percent reduction. For both forms, improvement was statistically significant. For nausea alone, the difference in effectiveness between the two forms was quite small. For vomiting, however, the difference was larger, and smokers had somewhat greater improvement. One possible explanation for this was that some patients threw up the capsules shortly after receiving chemotherapy. Administering the pills earlier than 30 minutes before chemotherapy may offset this apparent advantage of smoking.
Prior to this study, some scientists suspected that patients who had previously used cannabis illicitly, perhaps as a mood-altering compound, would be more likely to show an antiemetic response. Forty-one percent of study patients had used it previously; the remainder had not. Contrary to expectation, those who had never used cannabis improved more than those who had. Prior users showed slightly less than 50 percent improvement, while those without prior use showed a change of slightly more than 50 percent. Another interesting result appeared in the nausea and vomiting ratings at baseline, immediately prior to dosing and four hours after dosing. Prior users had lower ratings of severity on both nausea and vomiting at all three times. This suggested that the patients in general were probably not exaggerating their discomfort just to get marijuana.
After the first test dose of cannabis or delta-9-THC, 90 percent of patients elected to continue on the study. We learned that prior users were more likely to continue whether on oral (96 percent) or inhaled form (95 percent). People who said they had not used cannabis before the study were more likely to continue if they were smoking (94 percent) than if they were taking the pills (82 percent). In other words, patients without prior use were three times more likely to drop out after initial dosing if they were taking pills than if they were smoking (18 percent versus 6 percent). Irrespective of dose form, patients with no prior use were three times more likely to drop out after the initial dosing than those with prior use (14 percent versus 4 percent).
The presence or absence of eight side effects of cannabis was tallied before and hourly after dosing for the four-hour observation period. The side effects were: euphoria (being "high"), sleepiness, agitation, depression, fearfulness, anxiety, visual and auditory hallucinations. The most common side effect was sleepiness. In fact, so many patients fell asleep that questions went unanswered. Of the approximately 90 patients who were awake, 50 percent reported sleepiness. About 45 percent reported feeling "high" at one and two hours after dosing. Before dosing, 14 percent had reported feeling agitated, declining to 10 percent at one hour and 13 percent at two hours. Of the patients in the study, 17 percent reported feeling depressed before treatment, but only 6 percent were at two hours. Before medication 15 percent reported being fearful and 45 percent felt anxious. Only 6 percent were fearful at one hour, less afterward. And only 21 percent were anxious at one hour, 18 percent at two hours and less afterward. Three patients reported hallucinations; one only before dosing. Of the two others, one was felt to have a heightened awareness of a piece of medical machinery in the room, and the other experienced a series of pleasant pictures. However, there were three cases of side effects requiring medical attention. Two patients had paranoid/fear responses after the four-hour observation period, and one had a strongly elevated heart rate due to an underlying heart condition. The first two situations were managed by simply talking to the patients and waiting for the medication to leave their system. The third problem was quickly resolved by the patient's physician, who had treated similar episodes in the patient in the past.
At the time of data analysis, 154 patients had finished the program with the remaining 15 still receiving medication. Forty-four patients stopped because they believed the cannabis or delta-9-mc capsules to be ineffective (29 percent). Thirty-four (77 percent) of those who stopped had been on the oral drug, the remainder smoked. Twenty-two patients (14 percent) stopped because of side effects; 17 of those patients (77 percent) were on oral medication. Forty-one patients stopped when chemotherapy was changed or discontinued, and 21 patients died in the course of treatment. The remaining patients failed to report their reason for stopping (Table 4).
The average patient received about 50 doses of medication (cigarettes or pills) while on the program. Patients on the oral form averaged 35 doses, and those on the inhaled form averaged 60. The latter amount is magnified because of a small group of patients on daily chemotherapy that produced mild to moderate persistent nausea. These values are below expectation, as we found that most patients reduced the number of pills ingested or cigarettes smoked to the minimum needed for comfort. Unused medication was returned to the pharmacy. However, there was one unsubstantiated allegation of a patient diverting the drug illegally.
A final issue has to do with patient "controls." Scientists like to measure the same variables in people not being treated as in those treated. In this study there were two such cancer patient groups: one group requested but was not able to receive the cannabis, and a second group did not request the cannabis even though the patients knew of its experimental availability. These two patient groups were asked to rate their nausea and vomiting at their most recent chemotherapy. There was no difference between the two on these symptoms. The two groups were then combined and compared with patients who received oral or inhaled medication. The experimental group was found to have significantly worse nausea and vomiting than the control group. This is as it should be, considering that the study aimed at working with "worst case" patients. When the type of chemotherapy was assessed (mild, moderate, or severe), there were far more people with severe chemotherapy in the experimental group than in the control group. And that fact probably accounted for why nausea and vomiting were also worse. An additional analysis comparing sex, stage of cancer, and prior use of marijuana showed no difference between the experimental and control groups. The results of this study thus seem to be reasonably honest, reliable, and accurate, given the many difficulties in conducting such an experiment.
Patient Examples
A 67-year-old man requested marijuana after having severe nausea and vomiting with several anticancer chemotherapy treatments with cis-platinum, a severe emetogenic agent. Several different conventional antiemetics failed to provide any relief. Except for his cancer and side effects of treatment, he was in good physical health. He denied ever having used marijuana or any other illegal drug, and he rarely used alcohol. He was a pipe smoker of many years and wanted to smoke the marijuana by pipe, instead of in a cigarette form. During his first dosing, he achieved moderate relief through smoking. He requested and was given a supply to take home. On follow-up he reported excellent control of his nausea and vomiting, indicating that he even ate small meals without nausea or vomiting within hours of receiving chemotherapy. Moreover, he experimented with his doses and found that he could inhale just small amounts and suppress his symptoms for several hours. In this fashion, he used much less marijuana than prescribed and, of course, returned the unused portion for "someone else to use." That, of course, could not be done.
Ms. T. was a 35-year-old cancer patient who initially smoked marijuana at the suggestion of a friend to treat her nausea and vomiting. She was taking chemotherapy considered moderately emetogenic but was having far worse symptoms than expected for the classification of "moderate." She received delta-9-THC in capsule form and slept through her next chemotherapy session. At home, she cut the dosage to the minimum available, one capsule every four to six hours, and achieved excellent results over the next six months of treatment. Her cancer went into remission, chemotherapy was stopped, and she left the program to continue her life.
A young man with severe cancer initially received the pills, but threw up shortly after swallowing them. He is a nonresponder for the purposes of the study, but he was allowed to smoke at a later chemotherapy session. He then attained very good control of his symptoms, but this is not reflected in the data presented. There were other patients who faced similar problems with the capsules and who refused to smoke. Some patients could not tolerate the smoke and were switched to the capsules. Some did well, some did not, but all patients were very appreciative of having the chance to try the medication in either form regardless of whether the treatment was successful.
Appetite
The data on appetite was obtained in the same manner and under the same conditions as described above. The same baseline of most recent chemotherapy versus four hours after receiving the marijuana dose applied. Overall, there was a statistically significant difference, indicating that appetite was less of a problem after using marijuana or delta-9-THC than after using conventional antiemetics for chemotherapy side effects. The average baseline measure was in the moderate to severe range of difficulty. The typical improvement was about 30 percent to 40 percent. But there were some differences, depending on the severity of chemotherapy-induced nausea and vomiting. Patients on mild and moderate emetogenic chemotherapy showed more improvement than those on chemotherapy rated as severe. This is consistent with the results for nausea and vomiting.
Next, the oral form was compared to the inhaled form, and the improvement was found to be identical, roughly a 20 percent change. This does not seem like much at first, but it must be kept in mind that these patients were predominantly concerned with nausea and vomiting and, to some extent, were experiencing these symptoms despite the use of cannabis. Hence, they may not have been as attentive to their appetite, or their nausea and vomiting made it difficult to have much appetite.
The data were scrutinized closely to see if there was a correlation between chemotherapy severity and the form of medication. It was found that patients receiving mild or moderately severe emetogenic chemotherapy showed the best improvement, about 30 percent to 40 percent, whether they were smoking or taking pills. Those on severe chemotherapy improved the least, only about 10 percent, and those smoking had less improvement than those taking the pills. There are, however, differences in how the body handles inhaled drugs compared to those taken orally, especially as regards cannabis and delta9-nic. For example, a breakdown product of delta-9-THC, whether entering the body orally or by inhalation, tends to be higher after oral ingestion. Thus, it may be the metabolite rather than the original drug that accounts for appetite stimulation. It also must be remembered that people who use cannabis recreationally report appetite stimulation some hours after ingesting the drug. Therefore, our four-hour measurement period may not have included the best time to assess this effect. It is quite possible that a different type of study is necessary to demonstrate more effectively the appetite stimulating properties of marijuana, if this has not yet been done.
As mentioned above, there was a control group that could be compared to the experimental group in terms of severity of appetite problems. Briefly, there was no difference. Both groups rated their appetite problems as moderate to severe in intensity. However, it was not possible to measure the control group's appetite during chemotherapy and treatment with conventional antiemetics. Hence, a gap in knowledge does exist here.
Patient Examples
Mr. Z. was a middle-aged man, who had developed a serious stomach cancer ind was slowly dying. His appetite was poor, and his weight loss accelerated after nausea and vomiting from chemotherapy. Cure of his cancer was a very remote prospect. He asked for marijuana, so he could have "more time" with his family, thinking that if he could relieve his nausea and vomiting even a little, his weight would stabilize. Decades before, he had smoked marijuana once or twice and so chose that route for his treatment. Not only did he have good control of nausea and vomiting, but he proudly announced that he had "eaten his first steak in months" because his appetite returned. For humanitarian reasons, he was approved to smoke daily at each meal, and his weight stabilized, then increased. On two occasions the delivery of marijuana supplies to him was delayed, and without the appetite stimulation, his weight began to fall each time. It is nice to imagine that he did receive a positive response to his request for "more time" to be with his wife and children.
Ms. K. said the capsules did a very good job of controlling her nausea and vomiting side effects. But she was most pleased that she was finally able to eat, as her appetite returned with the medication. In fact, she was able to reduce the amount needed to control nausea and vomiting so that the extra capsules could then be used to get her appetite and weight up between chemotherapy treatments. Her biggest problem was a close relative, who was shunning her as a "drug addict" because of the capsule. Since it was crucial for her to complete the entire course of chemotherapy, lasting many more months, time was taken to educate the relative about the therapeutic use of the drug versus its recreational use. Ms. K. did complete her prescribed course of cancer treatment with the full support and encouragement of the relative.
Summary
The Lynn Pierson Therapeutic Research Program was a unique opportunity to assess the medical uses of a Schedule I illegal drug with "no known medical use." The results achieved strongly indicate that both the inhaled natural cannabis and the pill form of its active ingredient, delta-9-THC, are effective for control of nausea and vomiting as well as for appetite stimulation. I think that if Lynn Pierson could read this chapter today, he would smile knowingly and approvingly.
References
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