Amelioration of Cancer Chemotherapy-InducedNausea and Vomiting by Delta-9-Tetrahydrocannabinol

The antinausea and antivomiting effects of delta-9-tetrahydrocannabinol (THC) in children receiving cancer chemotherapy were compared with those of metoclopramide syrup and prochlorperazine tablets in two double-blind studies. THC was found to be a significantly better antinausea and antivomiting agent, but not all patients obtained relief of nausea and vomiting with THC. In some patients, THC enhanced appetite during a course of chemotherapy. In two patients, a "high" associated with THC administration was reported. Drowsiness was reported significantly more frequently with THC.

Nausea and vomiting resulting from the administration of cancer chemotherapeutic agents are one of the major causes of morbidity, and seriously diminish the quality of life during treatment which may last from six months to two years Currently available antiemetic agents usually do not effectively control these symptoms. Sallan et alii have reported that oral administration of delta 9 tetrahydrocannabinol (THC), when compared with a placebo, caused a significant reduction in the frequency of nausea and vomiting (1).

This paper reports two double blind studies in which the antiemetic properties of THC were compared with those of Metoclopramide (Maxolon) and prochlorperazine (Stemetil).

Patients and Methods

Nineteen children with various neoplastic diseases requiring chemotherapy were entered into the study which compared the antiemetic effects of THC with those of metoclopramide. Informed consent was obtained from the parents and the children, who were informed that THC was a purified form of marihuana. THC was obtained in a limited amount, in the form of brown 5 mg and 2.5 mg capsules. Included in the first study were 15 males and four females. Their ages ranged from five to 19 years with a median age of 11 years The study was designed to be double blind. As THC was presented in the form of brown capsules and metoclopramide could not be obtained in the same form it was decided to dispense metoclopramide in the form of a syrup at a concentration of 1 mg/ml. Placebo capsules made of soft gelatin containing peanut oil and placebo syrup were dispensed together with the antiemetic preparations Thus, the patients were taking either THC and placebo syrup or metoclopramide syrup and placebo capsules. THC was administered in a dose of 10 mg/m2 with a maximum dose of 15 mg. It was given two hours before chemotherapy and at four, eight, 16 and 24 hours after the first dose. Metoclopramide was given in a dose of 10 mg for patients with body surface area (SA) greater than 0.7 m2, and in a dose of 5 mg for patients with SA less than 0.7 m2. It was given on the same time schedule as THC but, to prevent neurological toxicity the four hour dose was always a placebo.

To compare the antiemetic properties of the two agents in the same patients receiving the same chemotherapy, a crossover study was designed. For 50 patients, five consecutive courses of the same chemotherapy were randomized so that the patients received antiemetic agents in all possible combinations, except those which allowed the use of the same antiemetic on five consecutive occasions Thus, patients could receive any of eight combinations (for example, THC, THC, THC, THC, metoclopramide (M); or THC, THC, THC, M, M or THC, THC, M, M, M, and so on) Patients who received at least one course of THC and one of metoclopramide during repeated courses of the same chemotherapy were considered suitable for analysis in the crossover studies

During the course of the first study, it seemed likely that one of the agents was associated with a high incidence of post chemotherapy nausea and vomiting which caused patients to refuse to continue with the study. When the code was broken, this was found to be metoclopramide. In eight patients, it was possible to compare the effects of metoclopramide and THC by the crossover method.

With the remainder of the THC, a new double blind study was undertaken, this time comparing the antiemetic effect of THC with prochlorperazine. After informed consent, 14 other patients were entered into the study, seven males and seven females, whose ages ranged from six to 19 years, with a median age of 14 years. In this study, crossover was possible in seven children.

The design of this study was altered only by eliminating placebo syrup and replacing it with placebo tablets of an identical appearance to prochlorperazine The doses of prochlorperazine were as follows: for children with SA from 0.7 m2 to 1.1 m2 - 5 mg two hours before chemotherapy, a placebo four hours after chemotherapy, and 5 mg at eight, 16, and 24 hours after chemotherapy, for those with SA from 1.1 m2 to 1.4 m2 - 10 mg two hours before chemotherapy, a placebo four hours after chemotherapy, 10 mg at eight hours, and 5 mg at 16 hours and 24 hours after chemotherapy for those with SA greater than l.4 m2 all doses were l0 mg with placebo given at four hours after chemotherapy.

The results of the study were analyzed by asking the patients and the family to complete a questionnaire which assessed presence or absence of nausea, anorexia and drowsiness, frequency of vomiting, and the presence of symptoms suggestive of a "high." The family and patients were asked to note unusual euphoria, agitation, dreams or altered behavior. When patients were admitted to hospital, or received chemotherapy in the day treatment room, response was assessed by the nurses. Significance of difference in symptoms was analyzed by Fisher's exact probability test.

Results

In the first study, the code was broken before equal numbers or episodes had been randomized. Thus, 17 courses of anticancer chemotherapy were randomized to receive THC and 25 courses to receive metoclopramide. Patients were treated with essentially similar chemotherapy regimens (Table 1 ). There was significantly lower incidence of nausea, vomiting, and anorexia in the THC group. Drowsiness was reported more often in THC treated patients (Table 2). In eight patients, there was crossover of anti-emetic drugs (Table 3). Patients who received THC had significantly less nausea and vomiting, but reported drowsiness significantly more often. In the crossover episodes, there was no significant difference in the reports of anorexia, but an increase in appetite was reported only in the THC group on four occasions.

In the second study, 18 episodes were randomized to receive THC and 18 to receive prochlorperazine. Patients were treated with essentially similar chemotherapy regimens (Table 4). The results are shown in Table 5. There was a significantly lower incidence of nausea and vomiting, and an increase in the incidence of drowsiness in the THC group. There was no significant difference in the incidence of anorexia, but three patients who were receiving THC reported an increase in appetite.

In seven patients, crossover of antiemetic drugs was possible. Nausea and vomiting were significantly less frequent in the THC group, while drowsiness was more common. There was no significant difference in the incidence of anorexia.

Agitation, anxiety, and bad dreams were reported by only one patient who was receiving THC. Another patient reported a feeling of euphoria, lightness and increased appetite. The only other cerebral effects noted consistently were drowsiness.

Discussion

The results of this study demonstrate that in patients receiving cancer chemotherapy, THC is a significantly better antiemetic agent than either metoclopramide syrup or prochlorperazine tablets. The superior effect of THC may be ascribed to its pharmacological properties or to a more effective dose schedule for THC than for the other agents. The doses of metoclopramide and prochlorperazine used in this study were the maximum that can be safely administered to children. Thus, within the safe therapeutic range, THC appears a superior antiemetic agent. In the first study, metoclopramide was dispensed in the form of a syrup. This proved to be an unfortunate choice of presentation, as patients claimed that the appearance and texture of a syrup was nauseating. In the second study, this problem was overcome by using tablets, and THC was once again shown to be a superior antiemetic agent.

THC appeared to be effective in controlling nausea and vomiting with diverse chemotherapeutic regimens, including high dose methotrexate (7.5 g/m2) and combination chemotherapy with drugs such as nitrogen mustard, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisolone. Not all patients however, obtained complete relief of vomiting with THC. From this study, we are unable to assess what factors may predict a failure to respond to THC.

Only two patients reported a "high" while receiving THC. In one patient, this proved so unpleasant that further treatment with THC was refused. Drowsiness, however, was more common in the THC treated patients. The "high" with marihuana is usually biphasic and includes a phase of drowsiness. As this study was conducted in children, it is possible that the hallucinatory effects were reported because of difficulty in understanding and expressing these symptoms by children in this age group. The only undesirable short term side effect of THC was a bad "trip" in one patient. As, in many patients, THC is more effective than currently available antiemetics, its use in cancer chemotherapy under medical supervision appears warranted.

References

1. Sallan, S E, Zinberg, N E, and Frei, E. Antiemetic effect of delta 9 tetrahydrocannabinol in patients receiving cancer chemotherapy. New Engl J Med, 1975, 293 795
2. Hallister, L E. Structure activity relationships in man of cannabis constituents and homologs and metabolites of delta 9 tetrahydrocannabinol. Pharmacology, 1974, 11: 3