Abstract

Delta-9-tetrahydrocannabinol (THC) is an effective antiemetic as compared with placebos in patients receiving chemotherapy for cancer. In this study we compared THC with prochlorperazine (Compazine) in a randomized, double-blind, crossover trial with patients who had failed to benefit from standard antiemetic therapy. Regardless of the emetic activity of the chemotherapeutic agents, there were more complete responses to THC courses (in 36 of 79 courses) than to prochlorperazine (in 16 of 78 courses). Of 25 patients who were treated with both drugs and who expressed a preference, 20 preferred THC (P = 0.005). Among patients under 20 years of age there was a higher proportion of complete responses to THC courses (15 of 20) than among older patients (21 of 59 courses; P = 0.004).

Increased food intake occurred more frequently with THC (P = 0.008) and was associated with the presence of a "high." Of 36 THC courses resulting in complete antiemetic responses, 32 were associated with a high.

We conclude that THC is an effective antiemetic in many patients who receive chemotherapy for cancer and for whom other antiemetics are ineffective.

Nausea and vomiting of central origin occur after the administration of a variety of chemotherapeutic agents for cancer and frequently constitute the major illness resulting from such treatment. Control with classic antiemetics has been incomplete and variable (1).

Phenothiazines have traditionally been the drugs of choice in both the control and prevention of vomiting. Controlled studies of the antiemetic effects of phenothiazines in patients receiving chemotherapy for cancer have demonstrated that the phenothiazines are more effective than placebos but generally do not adequately control nausea and vomiting (2). Another oral agent, delta-9- tetrahydrocannabinol (THC, the active ingredient of marihuana), has been shown to have antiemetic properties superior to those of placebos in reducing vomiting caused by chemotherapy (3). In addition, THC has been proved to stimulate appetite and food consumption (4).

The purpose of this study was to compare the effects of orally administered THC with the effects of prochlorperazine (Compazine), one of the most commonly prescribed phenothiazine antiemetics, on nausea and vomiting in patients receiving chemotherapy for cancer.

Methods

Eighty-four patients known to have neoplasms were enrolled in the study. Fifty-one were male and 33 female, and their ages ranged from nine to 70 years (average age, 32.5 years). All but two patients had received previous chemotherapy (including doxorubicin, cyclophosphamide, high-dose methotrexate, cisplatin, bleomycin, and vinblastine), their nausea and vomiting were inadequately controlled by conventional antiemetics, including the phenothiazines. Pregnant women and patients with a history of emotional instability or untoward reactions to psychoactive drugs were not eligible.

The study was thoroughly explained to the patients. They were told that they would receive either a conventional antiemetic or a marihuana-like drug to control nausea and vomiting. Five subjects known to use marihuana agreed not to smoke it during the course of the study.

THC was supplied by the National Institute on Drug Abuse. The drug was suspended in 0.12 ml of sesame oil and supplied in gelatin capsules to blind the study. The THC dosage was 10 mg per square meter of body-surface area, with 15 mg the amount most commonly administered. On the basis of our previous experience with variability of response, the five patients with body-surface areas of less than 1 square meter each received 10 mg of THC (3). Prochlorperazine tablets were crushed, and 10 mg of the drug was placed with a filler of powdered lactose into opaque capsules that were identical in appearance to those containing the THC.

The experimental plan was a randomized, double-blind design in which each patient was to receive three one-day courses of a study drug (two courses with one drug and one course with the other). Neither the person administering the drug nor the one recording the patient's response knew which drug the patient received. The study days were arranged so that chemotherapy regimens were the same for each of the three courses. If the chemotherapy changed, the patient was not evaluated for comparison. Each drug course consisted of three doses given every four hours; the first dose was administered one hour before chemotherapy, and the other two doses three and seven hours after chemotherapy,. Each patient was randomized to one of the six distinct ways of arranging two drugs in a sequence of three trials: TTP, PPT, TPT, PTP, TPP, or PTT, where T refers to THC and P to prochlorperazine. In this way any effects of order were balanced.

Nausea, vomiting, food intake, and the development of a "high" were assessed by the patient on the day after treatment through the use of a self-administered questionnaire (the questionnaire is available to readers on request). In addition, the patient, nurses, and other ward and clinic personnel in contact with the patient were interviewed by one of the authors, who also reviewed the questionnaire and nurses' notes.

On the basis of responses to the questionnaires, the antiemetic effect of each study drug was rated as one of the following: complete response, defined as no nausea or vomiting after chemotherapy; partial response, a reduction in the severity of nausea and vomiting; or no response, no reduction in the severity of nausea and vomiting. Food intake during the 24 hours after chemotherapy was rated by the patient as no food intake, less than usual, average, or more than usual. Patients indicated whether or not they had become high and were asked to describe the condition if they so desired. For the purpose of this study, a high was characterized as a mood change that consisted of a tendency to laugh, elation, heightened awareness, mild aberrations of fine motor coordination, or minimal distortion of activities and interactions with others.

The significance tests reported in this paper are all two-sided tests. They are either tests associated with 2-by-2 contingency tables or the sign test. All P values were computed with exact tests.

Results

To assess the antiemetic activity of the two study drugs, the analysis was carried out in two parts. Patients who received both antiemetics were analyzed according to their antiemetic preference, whereas patients who received only one antiemetic were analyzed by means of comparison with other patients. The analysis of preference is more precise because it supplies information on the individual patient, thus eliminating many variables. The results were further assessed on the basis of emetic potential of the chemotherapeutic agents administered and the development of a high.

The study randomized 84 patients; however, not all patients completed the assigned three courses of drug treatment (Table 1).

Twenty-seven patients received only one course and were removed from the study for various reasons: two died of cancer; four had THC toxicity, characterized as being too high; one refused to accept the risk of vomiting with subsequent courses of other antiemetics after having a complete response to THC; seven had changes in chemotherapy regimens and thus became ineligible for comparison according to study criteria; and the remaining 13 patients vomited during the first course and chose to quit the study. Of these 27 who were removed from the study, 15 had received THC, and 12 prochlorperazine. Six patients had a complete response, and nine had no response to THC; with prochlorperazine, one patient had a complete response, and 11 had no response. The rate of complete response to THC (six patients of 15) was significantly higher than the rate for prochlorperazine (one patient of 12; P = 0.05). All six patients who had complete responses to THC became high, whereas only two of the nine patients who had no response to THC became high.

Response and preference may depend on the emetic activity of the chemotherapeutic agents that the patient is taking. Various cancer drugs and drug combinations were separated into classes A, B, and C; class A includes the strongest emetics, class B the moderate emetics, and class C the weakest emetics (Table 2).

The response to THC and prochlorperazine as a function of the total number of antiemetic courses and class of emetic activity is summarized in Table 3. This analysis compares responses between patients and not within individual patients and thus reflects the antiemetic effect regardless of the number of study courses completed. Complete responses resulted from 36 of 79 THC courses and 16 of 78 prochlorperazine courses.

The antiemetic preferences of patients who received two or three drug courses are summarized in Table 4. Of 25 patients who expressed a preference, 20 preferred THC to prochlorperazine (P = 0.005). The degree of preference for either antiemetic did not depend on the class of emetic activity of the patient's chemotherapy for cancer. However, eight patients without an antiemetic preference took class A treatments, as compared with 13 who took class B and C treatments. This trend was not statistically significant (P = 0.14)

The antiemetic response to THC correlated with the development of a high. As summarized in Table 5, 32 of 41 courses associated with a high also resulted in a complete response, whereas only four of 38 courses without a high resulted in a complete response (P<0.0001). <p /> The ages of patients in each antiemetic group having more than one course are the same by virtue of the experimental design. The average ages of the single-drug groups are 34.2 years for THC and 33.4 years for prochlorperazine. An analysis of response by age showed that THC was superior to prochlorperazine in patients of every age. The rate of complete response to prochlorperazine, 16 courses of 78, did not change markedly with age. On the other hand, complete responses to THC numbered 15 of 20 for patients under 20 and 21 courses of 59 for patients 20 or older (P = 0.004).

Food intake after chemotherapy was evaluated in 28 patients who completed three courses of antiemetic therapy. Responses were obtained from the questionnaire and were categorized into one of three outcomes: more food intake with THC, more food intake with prochlorperazine, or the same food intake with both drugs. Table 6 summarizes the preferences of the patients according to occurrence of a high and of increased food intake. Eight of the 28 patients ate more during the prochlorperazine courses, and 19 ate approximately the same amount during all courses. We found a very strong association between increased food intake during the THC course and the presence of a high. Eight of 16 patients who became high reported an increased food intake that was conditional on the high; none of the 12 who failed to become high reported a greater intake (P = 0.008).

Discussion

The results of this randomized, double-blind study demonstrate that THC is superior to prochlorperazine as an antiemetic in patients receiving chemotherapy for cancer. However, our conclusions are conditional in that the patients in this study were presumed refractory to conventional antiemetics including the control drugs, the phenothiazines. Of these presumed refractory patients, 23 had a complete or partial response to prochlorperazine. This variability of response is consistent with experimental evidence in the prevention of apomorphine-induced vomiting in normal human volunteers. In those volunteers the same doses of apomorphine had different emetic effects, and the same doses of antiemetics had variable antiemetic effects (5).

Failure to attain a high after ingesting oral THC and the concomitant absence of an antiemetic effect may be explained by either pharmacologic or psychologic phenomena. Relatively little is known about human gastrointestinal absorption of this highly water-insoluble cannabinoid. Oral administration may result in erratic absorption, thereby precluding standardization of the THC dose. Plasma levels would provide important information in determining THC activity. An attempt to correlate the antiemetic activity of THC with its plasma concentrations has demonstrated the existence of a relatively steep dose- response curve (6). Variability in achieving a high has been reported in subjects who have never used marihuana. Many persons do not become high on their first exposure to marihuana, as has been reported anecdotally by regular users over the years (7). It has been hypothesized that prior pharmacologic sensitization or repeated exposure to marihuana reduces psychologic inhibition and is necessary to experience a high state.

We attempted to evaluate the influence of the study day on the antiemetic effect by examining patients who had different responses to the same antiemetic drug on different study days. We found that there was no influence of drug sequences on response, which supports the findings of Herman et al (8). As in our previous study, the time of onset and duration of the high were unrelated to previous marihuana use (3). However, one patient who had used marihuana routinely before the study found the intensity of the THC high to be much greater than that previously induced by marihuana, possibly because of the development of a reverse tolerance (9). He found the THC high unpleasant and refused further THC treatment after the first study day. It is important to note that except in the previously mentioned four patients who had THC toxicity, no side effects of either study drug were reported by any patient. The absence of reports of somnolence differs from our initial experience (3). Although we observed somnolence in some patients, we cannot explain their failure to report it.

Synthetic analogues of THC, such as the cannabinoid nabilone, are also potent antiemetics. A recent study comparing prochlorperazine with nabilone showed that nabilone was superior to prochlorperazine in controlling nausea and vomiting induced by chemotherapy (8). A limited number of our patients who responded favorably to THC have continued using the drug during subsequent chemotherapy. Several of these patients have reported a diminution in the antiemetic effect of THC with repeated doses. This anecdotal finding contradicts a previous report (9) of the development of reverse tolerance in persons who use marihuana often. THC analogues may prove advantageous if they appear effective with repeated courses of chemotherapy.

We attempted to correlate the degree of emetic activity of the chemotherapeutic agents with the extent of response to the antiemetic agents. Although THC was apparently a better antiemetic than prochlorperazine, no distinction could be drawn between the degree of antiemetic activity and the degree of emetic stimulation. This finding agrees with the results from studies of nabilone, (8) indicating that both THC and nabilone provide antiemetic activity against many chemotherapeutic agents.

Experimental evidence demonstrating the antiemetic effects of both chlorpromazine and THC has been reported by ten Ham and de Jong (10). Using animal models of stereotypic behavior after apomorphine administration, they compared the activity of THC with that of chlorpromazine in Wistar rats and homing pigeons. Whereas THC was shown to antagonize low doses of apomorphine but not high doses, chlorpromazine appears to have a very strong antiapomorphine effect, even at high doses of apomorphine. Further studies of the pharmacology of THC and other cannabinoids in monkeys, dogs, and other laboratory animals are ongoing. However, it is important to consider species differences in vomiting behavior. Some laboratory animals, such as monkeys, are known to be poor models for vomiting, (11) and the so-called crop vomiting of pigeons may have an entirely different mechanism from that of the vomiting activity of mammals (12).

In summary, these data demonstrate that THC is a safe and effective antiemetic for patients receiving chemotherapy for cancer. In many patients, THC was comparable to the most commonly used phenothiazine, and THC was preferred by most patients who expressed preferences. Failure to respond to THC may be due to pharmacologic factors such as failure of absorption. THC can be used safely at a dosage of 10 mg per square meter every four hours for at least three doses. Further investigation is indicated for THC and other cannabinoid derivatives, alone and in combination with other approaches to the control of vomiting in patients receiving chemotherapy.

References

1. Browne DC, Sparks R. Vomiting mechanisms: a clinical study of thiethylperazine. South Med J. 1961; 54:953-61.
2. Moertel CG, Reitemeier RJ. Controlled clinical studies of orally administered antiemetic drugs. Gastroenterology. 1969; 57:262-8.
3. Sallan SE, Zinberg NE, Frei E III. Antiemetic effect of delta-9-tetrahydrocannabinol in patients receiving cancer chemotherapy. N Engl J Med. 1975; 293:795-7.
4. Hollister LE. Hunger and appetite after single doses of marihuana, alcohol, and dextroamphetamine. Clin Pharmacol Ther. 197 1; 12:44-9.
5. Shields KG, Ballinger CM, Hathaway BN. Antiemetic effectiveness of haloperidol in human volunteers challenged with apomorphine. Anesth Analg (Cleve). 1971; 50:1017-27.
6. Chang AE, Shiling DJ, Stillman RC, et al. A prospective evaluation of delta-9-THC as an antiemetic in cancer patients receiving high dose methotrexate. Ann Intern Med. (in press).
7. Weil AT, Zinberg NE, Nelsen JM. Clinical and psychological effects of marijuana in man. Science. 1968; 162:1234-42.
8. Herman TS, Einhorn LH, Jones SE, et al. Superiority of nabilone over prochlorperazine as an antiemetic in patients receiving cancer chemotherapy. N Engl J Med. 1979; 300:1295-7.
9. Lemberger L, Tamarkin NR, Axelrod J, Kopin IJ. Delta-9-tetrahydrocannabinol: metabolism and distribution in long-term marihuana smokers. Science. 1971; 173:72-4.
10. ten Ham M, de Jong Y. "Anti-emetic" activity of tetrahydrocannabinol in rats and pigeons. N Engl J Med. 1978; 298:798-9.
11. Borison HL. Animal techniques for evaluating antiemetic drugs. In: Nodin JH, Siegler PE, eds. Animal and clinical pharmacologic techniques in drug evaluation. Chicago: Year Book, 1964: 418-22.
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V. Tables

Table 1.
Summary of Patients According to Number of Treatment Courses Completed

Classification of Patients	No. of Patients	Characteristics
Total Registered	84
Ineligible for study	11	4 vomited before chemotherapy; insufficient data for 7
Completed 1 course	27	15 received THC; 12 received prochlorperazine
Completed 2 courses	8	Each patient received THC and prochlorperazine
Completed 3 courses	38	56 courses of THC; 58 courses of prochlorperazine

Table 2.
Classification of Chemotherapeutic Agents According to Emetic Activity

Class
A.	Greatest emetic activity Combinations of agents inclucing cisplastin, dacarbazine, doxorubicin, and cyclophosphamide
B.	Moderate emetic activity Combinations of agents including high-dose methotrexate, cyclophosphamide, doxorubicin, and actinomycin D. Cisplatin and high-dose actinomycin D as single agents
C.	Least emetic activity Single agents including high-dose methotrexate, cyclophosphamide, and doxorubicin

Table 3.
Response of Patients to Antiemetics According to Emetic Activity of Patients' Chemotherapy

Emetic Activity	Antiemetic	Complete Response	Partial Response	No response	Totals
	No. of Courses
Class A	THC Pro	18(47) 7(19)	4(11) 9(25)	16(42) 20(56)	38 36
Class B	THC Pro	13(43) 8(25)	5(17) 4(13)	12(40) 20(63)	30 32
Class C	THC Pro	5(45) 1(10)	1(19) 2(20)	5(45) 7(70)	11 10
Subtotals	THC Pro	36(46) 16(21)	10(13) 5(19)	33(42) 47(60)	79 78
Totals		52(33)	25(16)	80(51)	157

Table 4.
Summary of Antiemetic Preferences of Patients Receiving Two or Three Courses of Antiemetics

Emetic Activity of Chemotherapy	THC Preference	Prochlorperazine Preference	No Preference	Totals
	No. of Patients
Class A	13 (54)	3 (13)	8 (33)	24
Class B	5 (29)	1 (6)	11 (65)	17
Class C	2 (40)	1 (20)	2 (40)	5
Totals	20 (43)	5 (11)	21 (46)	46

Table 5.
Response to THC Related to Development of High

	Complete Response	Partial Response	No Response	Totals
	No. of Courses
High	32 (78)	4 (10)	5 (12)	41
No High	4 (11)	6 (16)	28 (74)	38
Totals	36 (46)	10 (13)	33 (42)	79

Table 6.
Antiemetic Preference Related to Food Intake and Development of a High

Antiemetic Preference	High		No High		Totals
	Increased Food Intake	Same Food Intake	Increased Food Intake	Same Food Intake
	no. of patients
THC	6	3	0	2	11
Prochlorperazine	0	1	0	2	3
None	2	4	0	8	14
Totals	8	8	0	12	28