Vincent Vinciguerra, MD; Terry Moore, MSW; Eileen Brennan, RN

October 1988/ New York State Journal of Medicine pp. 525-527

ABSTRACT: A prospective pilot study of the use of inhalation marijuana as
an antiemetic for cancer chemotherapy was conducted. Fifty-six patients
who had no improvement with standart antiemetic agents were treated and 78%
demonstrated a positive response to marijuana. Younger age and prior
marijuana exposure were factors that predicted response to treatment.
Toxicity was mild and consisted primarily of sedation and xerostomia. This
preliminary trial suggests the usefulness of inhalation marijuana as an
antiemetic agent. Because of the lack of a randomized placebo control
group, the precise role of this agent is unclear. Further studies should
include derivatives of this substance in combination with standard
effective drugs to control chemotherapy-induced nausea and vomiting.

(NY State J Med
1988; 88: 525-527)

>From the Don Monti Division of Oncology, Department of Medicine, North
Shore University Hospital, Manhasset, NY, and the Department of Medicine,
Cornell University Medical College, New York, NY.
Address correspondence to Dr. Vinciguerra, Chief, Division of
Oncology/Hematology, North Shore University Hospital, 300 Community Dr,
Manhasset, NY 11030.
Supported in part by the Don Monti Memorial Research Foundation, Community
Clinical Oncology Program (CCOP) grant #CA-53579, and the New York State
Department of Health.


A great deal of clinical information has recently been generated concerning
the efficacy of various antiemetic agents for patients treated with cancer
chemotherapy. (1-3). Without effective control of nausea and vomiting,
patient compliance with potentially curative chemotherapy programs
diminishes, compromising not only quality but quantity of life. Effective
new chemotherapeutic agents could never be successfully tested in clinical
trials if they possessed potent emetic side-effects.
Although a number of agents have recently been found to be active,
including metoclopramide, (4,5) haloperidol, (6) dexamethasone, (7) and
lorazepam, (8) the need to introduce newer agensts and combination
antiemetic therapy may be necessary for continued control of symptoms.
Also, complete control of nausea and vomiting during anticancer treatment
must take into account not only the physical effects but also the
psychological ones. Control of anxiety through behavior modification and
relaxation is an effective antiemetic treatment of anticipatory nausea and
vomiting. (9)

Natural and synthetic cannabinoids are known to be effective
antiemetic agents. (10-12) Delta-9-tetrahydrocannabinol (THC) has been
found to be superior to prochlorperazine. (13) Also, patients who are
refractory to standart antiemetic agents have significant reduction in
nausea and vomiting with oral THC. (14) There is little information on
the efficacy of inhalation marijuana aside from anecdotal reports from
patients who obtained the drug privately.
As a part of a New York State Department of Health program, North
Shore University Hospital conducted a preliminary study of the use of
inhalation marijuana as an antiemetic agent for cancer chemotherapy. The
purpose of this study was to evaluate the efficacy of inhalation marijuana
for patients refractory to standard agents, to identify patient
characteristics to predict response, and to evaluate toxicity and patient
acceptance of this form of treatment.

METHODS

Patients with histologically confirmed malignancies who were actively
receiving chemotherapy were entered into the protocol. Eligibility
criteria included: 18 years of age or older, refractoriness to
conventional antiemetic agents, and absence of severe cardiac or
psychiatric disease. Patients had to agree not to drive or operate heavy
machinery or a motor vehicle for at least 12 hours after the last dose of
marijuana. Central nervous system depressants including alcohol were
prohibited during the administration of marijuana.
Marijuana cigarettes were supplied by the National Institute on Drug
Abuse (NIDA) to the New York State Department of Health. All patients
were instructed on standard smoking procedures. The patient inhales
deeply, holds the inhalation for ten seconds, and then exhales. After
waiting 10 to 15 seconds, the cycle is repeated. The total dose is
completed within five minutes. A flame-proof holder was available to
permit delivery of nearly all of the cigarette appropriate to the patient's
dosage. The dose schedule, which was calculated to the nearest one-fourth
cigarette; was 5 mg THC/m2, starting 6-8 hours prior to chemotherapy and
every 4-6 hours thereafter, for a total dose of four doses per day on each
day of chemotherapy (one cigarette= 10.8 mg THC). In order to prevent
cigarettes from drying out and causing harsh smoke, patients were
instructed to keep the cigarettes in the refrigerator or humidified.
This was a nonrandomized study where patients served as their own
controls. Patients were asked to self-rate their status by completing a
patient evaluation form after each therapeutic episode. Nausea was graded
on a scale from 1 (none) to 4 (severe), vomiting was graded from 1 (none)
to 5 (10+ times), appetite was graded from 1(none) to 5 (above normal),
and physical state was graded from 1 (very weak) to 4 (above normal), and
mood was graded from 1 (very depressed to 5 (very happy). Based on the
degree of nausea, vomiting, food intake, physical state, and over-all mood,
patients rated the overall effectiveness of marijuana as none, moderately
effective, and very effective.
Physician investigators were approved by the Hospital's Patient
Qualification Review Board. Physicians utilized the official New York
State triplicate prescription form as their research order for medication.
Informed consent was obtained from all patients and the procedures followed
were approved by an institutional research committee.

RESULTS

Seventy-four patients entered the study and 56 were evaluable. Eighteen
patients who had initially agreed to be treated with marijuana later
decided not to participate. Eighteen patients rated the marijuana very
effective (34%) and 26 patients rated it moderately effective (44%) for
an overall response rate of 78% (44/56). Twelve patients (22%) noted no
benefit.


TABLE I. Patient Characteristics (Percent)


Responders Nonresponders P
Value
(N=44) (N=12)


Female 64 75
NS*
Mean age (yr) 41 51
(median) (40) (54)
Breast cancer 36 33
NS
Lymphoma 34 25
NS
Prior radiation therapy 30 8
NS
Prior THC 29 20
NS
Prior Marijuana 52 17
0.06
Euphoria 60 36
NS
(high)
Smoker 53 38
NS


*NS= not significant
Standard deviation= 11.9
Standard deviation= 15.6

Characteristics of responding and nonresponding patients are listed in
Table I. While no statistically significant differences were noted between
responders and nonresponders with regard to sex, type of diagnosis, prior
radiation therapy, prior oral THC treatment, incidence of euphoria, or
smoking history, it is important to remember that the sample sizes were
small, making interpretation of differences difficult. Patients who
responded to marijuana cigarettes were more likely to be younger, median
age 40 vs 54 for nonresponders, and had prior marijuana exposure, 52% vs
17% (p= 0.06).
The most common diagnoses for this group of patients were breast
cancer, lymphoma, lung cancer, colon cancer, ovarian cancer, testicular
cancer, sarcoma, acute leukemia, and myeloma. The most common emetic
chemotherapeutic agents were cyclophosphamide, doxorubicin, cis-platinum,
procarbazine, methotrexate, dacartazine, and streptozocin, given either
singly or in combination. Four of seven patients treated with cis-platinum
responded favorably to marijuana cigarettes.
Toxic side effects included sedation in 88%, dry mouth in 77%,
dizziness in 39%, and confusion in 13%. Anxiety, headache, and fantasizing
were also seen but were less common. There was no toxicity in 13% of
patients (Table II).


TABLE II. Percent Toxicity


Sedation 88
Dry Mouth 77
Dizziness 39
Confusion 13
Anxiety 11
Headache 11
Fantasizing 11
None 13


DISCUSSION

The results of this prospective study suggest that inhalation
marijuana is active in controlling nausea and vomiting resulting from
chemotherapy. Marijuana benefited patients who were treated with a wide
range of chemotherapeutic agents including drugs which have considerable
emetogenic potential. A prior report by Chang et al (15) documented
effectiveness of oral THC and inhaled marijuana against high-dose
methotrexate, which normally has mild gastrointestinal toxicity. While
most experience indicates that THC is generally ineffective against
cis-platinum-induced emesis, benefit was seen in a small number of patients
treated in our program with this agent.
Since this was a single arm, nonrandomized, outpatient program, this
study lacks a controlled placebo group. Nevertheless, the patients acted
as their own controls, having previously failed standard antinausea
medications. They evaluated marijuana based on their subjective rating of
the severity of nausea, vomiting, appetite and food intake, mood, and
physical state after chemotherapy treatment. A placebo-controlled,
randomized inpatient study which quantitates all emetic episodes would
obviously provide objective and precise information. (16)
Failure to respond to oral THC does not preclude benefit from inhaled
marijuana. Twenty-nine percent of patients who failed oral THC responded
to the cigarette form. This is not unexpected, since only 5-10% of orally
administered THC is absorbed, whereas inhaled marijuana has a five-to
tenfold greater bioavailability. (17) Clearly, oral THC is an effective
treatment for chemotherapy-induced emesis. Most studies have demonstrated
THC to be better than placebo and comparable to prochlorperazine. (18)
The major obstacle related to the oral and inhaled cannabinoids is the
route of administration. Patients with anticipatory vomiting do not retain
the oral THC. Because of its poor water solubility, parenteral
adminstration of cannabinoids has been difficult. The only cannabinoid
available for parenteral use, levonantradol, is currently being
investigated and has documented activity comparable to THC. (19) Perhaps
intranasal or transdermal forms of THC will be developed and found to be
clinically useful.
Patient characteristcs were evaluated to identify factors which would
predict response to marijuana. There were no significant differences
between responders and nonresponders with regard to sex, diagnosis, prior
radiation therapy, prior THC ingestion, induced euphoria, and history of
cigarette smoking. The only factors that approached significance were
young age and prior marijuana intake. Unlike the experience with oral THC,
experiencing a euphoric high was not a prerequisite to obtaining the
antiemetic effect with marijuana. (20)
The mechanism of the antiemetic action of cannabinoids is unknown.
Inhibition of prostaglandin and cyclic adenosine monophosphate has been
suggested. Its major action is more likely related to its effect on the
brain, as marijuana causes central nervous system depression and impairment
of brain function. At the cellular level, cannabinoids interfere with the
synthesis of nucleic acids and chromosome proteins. (21)
Some of the problems encountered in this study which could influence
interpretation of the results were the low patient accrual and the fact
that nearly 25% of patients who initially consented refused to receive
treatment. Reasons for patients' refusal to participate included physician
and patient bias against smoking, harshness of smoke from the cigarettes,
and preference for oral THC capsules. The major objection was related to
the social stigma attached to the use of marijuana. Many patients rejected
the idea of "smoking pot" at home and exposing their children to the
implications of this type of medication. Should this therapy become
available in a different vehicle of administration, patient acceptance
would significantly improve.
Our results demonstrate that inhalation marijuana is an effective
therapy for the treatment of nausea and vomiting due to cancer
chemotherapy. A randomized, controlled trial would, however, be necessary
to accurately define the exact role of this drug. Toxic effects are well
tolerated and the availability of a parenteral form would improve patient
utilization of this agent. Future antiemetic protocols should include the
active ingredient of marijuana in combination with current effective
agents.

Acknowledgments. The authors thank Rosemarie Galderisi and Annie
Middleton for their assistance.


REFERENCES

1. Seigel LJ, Longo DL: The control of chemotherapy-induced emesis. Ann
Intern Med 1981; 95: 352-359.
2. Frytak S, Moertel CG: Management of nausea and vomiting in the cancer
patient. JAMA 1981; 245: 393-396.
3. Bakowski MT: Advances in anti-emetic therapy. Cancer Treat Rev 1984;
11: 237-256.
4. Meyer BR, Lewin M, Drayer DE, et al: Optimizing metoclopramide control
of cisplatin-induced emesis. Ann Intern Med 1984; 100: 393-395.
5. Kris MG, Gralla RJ, Tyson LB, et al: Improved control of
cisplatin-induced emesis with high-dose metoclopramide, and with
combinations of metoclopramide, dexamethasone, and diphenhydramine.
Results of consecutive trials in 225 patients. Cancer 1985; 55:
527-534.
6. Neidhart JA, Gagen M, Young D, et al: Specific antiemetics for
specific cancer chemotherapeutic agents: Haloperidol versus benzquinamide.
Cancer 1981; 47: 1439-1443.
7. Cassileth PA, Lusk EJ, Torri S, et al: Antiemetic efficacy of
dexamethasone therapy in patients receiving cancer chemotherapy. Arch
Intern Med 1983; 143: 1347-1349.
8. Bishop J, Oliver I, Wolf M, et al: Lorazepam: A randomized, double
blind, crossover study of a new antiemetic in patients receiving cytotoxic
chemotherapy and prochlorperazine. J Clin Incol 1984; 2: 691-695.
9. Morrow GR: Clinical characteristics associated with the development of
anticipatory nausea and vomiting in cancer patients undergoing chemotherapy
treatment. J Clin Oncol 1984; 2: 1170-1176.
10. Laszlo J: Tetrahydrocannabinol: From pot to prescription
[editorial]. Ann Intern Med 1979; 91: 916-918.
11. Stack P: The pharmacologic profile of nabilone: A new antiemetic
agent Ca Treat Rev 1982; 9 (suppl B): 11-16.
12. Frytak S, Moertel CG, O'Fallon J, et al: Delta-9-tetrahydrocannabinol
as an antiemetic for patients receiving cancer chemotherapy. Ann Intern
Med 1979; 91: 825-830.
13. Sallan SE, Cronin C, Zelen M, et al: Antiemetics in patients
receiving chemotheraply for cancer. A randomized comparison of
delta-9-tetrahydrocannabinol and prochlorperazine. N Engl J Med 1980;
302: 135-138.
14. Lucas VS, Laszlo J: Delta-9-tetrahydrocannabinol for refractory
vomiting induced by cancer chemotherapy. JAMA 1980; 243: 1241-1243.
15. Chang AE, Shilling D, Stillma RC, et al: Delta-9-tetrahydrocannabinol
as an ant;iemetic in cancer patients receiving high-dose methotrexate. Ann
Intern med 1979; 91: 819-824.
16. Carey MP, Burish TG, Brenner DE: Delta-9-tetrahydrocannabinol in
cancer chemotherapy: Research problems and issues. Ann Intern Med 1983;
99: 106-114
17. Nahas GG: Current status of marijuana research. Symposium on
marijuana held July 1978 in Reims, France. JAMA 1979; 242: 2775-2778.
18. Poster DS, Penta JS, Bruno S, et al: Delta-9-tetrahydrocannabinol in
clinical oncology. JAMA 1981; 245: 2047-2051.
19. Citron ML, Herman TS, Vreeland F, et al: Antiemetic efficacy of
levonantradol compared to delta-9-tetrahydrocannabinol for
chemotherapy-induced nausea and vomiting. Ca Treat Rev 1985; 69:
109-112.
20. Ungerleider JT, Andrysiak T, Fairbanks L, et al: Cannabis and cancer
chemotherapy. Cancer 1982; 50: 636-645.
21. Council on Scientific Affairs: Marijuana. Its health hazards and
therapeutic potentials. JAMA 1981; 246: 1823-1827.

INDEX HOME