|
Abstract: Fifteen patients with osteogenic sarcoma
receiving high-dose methotrexate chemotherapy were
studied in a randomized, double blind, placebo-controlled
trial of oral and smoked delta-9-tetrahydrocannabiriol
(THC) as an antiemetic. Each patient served as his or her
own control. Fourteen of 15 patients had a reduction in
nausea and vomiting on THC as compared to placebo.
Delta-9-tetrahydrocannabinol was significantly more
effective than placebo in reducing the number of vomiting
and retching episodes, degree of nausea, duration of
nausea, and volume of emesis (p < 0.001). There was a
72% incidence of nausea and vomiting on placebo. When
plasma THC concentrations measured < 5.0 ng/mL, 5.0 to
10.0 ng/mL, and > 10.0 ng/mL. The incidences of nausea
and vomiting were 44%, 21%, and 6%, respectively.
Delta-9-tetrahydrocannabinol appears to have significant
antiemetic properties when compared with placebo in
patients receiving high-dose methotrexate.
Nausea and vomiting are frequent and
distressing side effects of cancer chemotherapy. The
severity of these symptoms contributes to the decreased
ability of patients to undergo long-term chemotherapy
schedules and impairs their quality of life (1, 2). Despite
the magnitude of this problem, there have been few clinical
reports (3-11) investigating the effectiveness of various
antiernetics in controlling the nausea and vomiting
associated with chemotherapy. Conventional antiemetics,
when tested, have been relatively ineffective in reducing
these side effects.
Sallan and colleagues (7) were able to show
that oral-delta-9-tetrahydrocannabinol (THC) had
significant antiemetic properties in patients receiving
various chemotherapy regimens. As in previous antiemetic
studies, nausea and vomiting were assessed solely from
subjective impressions based on patient interviews the day
after each drug trial. The purpose of our study was to
examine in a randomized, double-blind, placebo-controlled
trial the efficacy of oral and smoked THC as an antiemetic.
To do this we obtained both objective and subjective data
during each drug trial. Serial blood samples were drawn
during the course of each trial to ascertain the effective
plasma concentration of THC needed to obtain an antiemetic
effect.
METHODS
PATIENT POPULATION
Fifteen patients with osteogenic sarcoma
treated by the Surgery Branch of the National Cancer
Institute were studied. Ten were males and five, females;
they ranged in age from 15 to 49 years (median, 24 years).
All patients had undergone surgical removal of their
primary tumor (14 amputations and one chest-wall resection)
and were disease free upon entry into the study. All
patients received adjuvant high-dose methotrexate therapy
with leucovorin calcium rescue at 3-week intervals for a
total of 18 months. Methotrexate was given at a constant
dose of 250 mg/kg in each patient. Before participating in
the study each patient was evaluated by a psychiatrist
(D.S.) to screen out those likely to have untoward
reactions to psychoactive drugs. The study was thoroughly
explained to each patient and signed informed consent
obtained. Each patient was told he or she would "blindly"
receive either placebo or "THC, a marijuana-type compound"
during the day of chemotherapy.
STUDY DESIGN
Each patient served as his or her own
control. Patients accepted into the study entered Phase I
and received THC three times and placebo three times during
the six subsequent hospital admissions for chemotherapy
infusion. The order of THC and placebo administration for
these six methotrexate infusions was randomized into three
paired trials of either placebo-THC or THC-placebo. At the
end of three paired trials, which took approximately 5 to 6
months to complete, patients were classified as "excellent,
"fair," or "nonresponders" to THC (see below) and entered
Phase II. In Phase II, "excellent" responders received
eight THC trials and two placebo trials during their next
10 courses of chemotherapy. The enriched sequence of THC
trials was designed to assess whether repeated trials of
THC resulted in continued antiemetic responses. If the
patient was a "fair" responder or "non responder" to THC.
The dose was increased by one third, and the patient
re-entered Phase I to see if additional benefits could be
obtained.
DRUG DOSE AND SCHEDULE
Delta-9-tetrahydrocannabinol capsules and
cigarettes were supplied by the National Institute on Drug
Abuse. The THC was suspended in sesame oil and placed in
gelatin capsules. Identical-appearing placebo capsules
contained only sesame oil. Placebo cigarettes were produced
by multiple extractions of natural marijuana with ethanol.
The active cigarettes were prepared from these placebo
cigarettes by injection of THC through a spinal needle;
each weighed 900 mg and contained 1.93% THC (about 17.4 mg)
(12). The odor and taste of a lit placebo cigarette were
identical to those of a marijuana cigarette.
Delta-9-tetrahydrocannabinol was
administered at a dose of 10 mg/m2 given orally every 3 h
for a total of five doses. The first dose was given at 0700
h. 2 h before the 6-h methotrexate infusion. All patients
had undergone an 8-h fast before chemotherapy infusion to
standardize pretreatment oral intake. In the event of a
vomiting episode, the patient was given a THC cigarette for
the remaining doses of that trial. Variation in the amount
of smoke inhaled by each patient was minimized by using a
standard inhalation technique (12). Each patient would hold
the inhalation for 10 seconds, then exhale; after a 50
second wait the cycle was repeated until the whole
cigarette was smoked. Most patients finished their
cigarettes within 8 mm. A dose modification was made only
in the event of a dysphoric reaction, in which case all
subsequent oral or smoked doses were decreased by one third
for that patient. Placebo drug administration was handled
in a similar fashion. Neither the patients nor the nursing
staff was informed which drug was being
administered.
PATIENT EVALUATION AND RESPONSE
CRITERIA
Data collection for each trial started at
0700 h and lasted until 2400 h the day of chemotherapy. A
member of the nursing staff rated the patient every hour by
completing an objective questionnaire that measured number
of vomiting episodes (an event producing > 30 mL of
emesis), number of retching episodes, volume of emesis,
degree of nausea (0 to 3 point scale: 0 = none; 1 =
slightly; 2 = moderately; 3 = greatly), duration of nausea,
and volume of oral intake. Similarly, once during each
wakeful hour, the patient completed a subjective
questionnaire rating the psychological "high" (0 to 3 point
scale: 0 = none; 1 = slightly; 2 = moderately; 3 =
greatly), degree of nausea, degree of comfort, and other
drug side effects (questionnaire available upon
request).
Four variables used to evaluate individual
responses to THC and placebo were the number of vomiting
and retching episodes, volume of emesis, degree of nausea,
and duration of nausea. The nausea and vomiting variables
on all completed paired THC trials and all placebo trials
in Phase I were summed. An "excellent" response was defined
as a > 80% reduction for all four nausea and vomiting
variables on THC as compared to placebo. A "fair" response
was defined as > 30% but < 80% reduction of at least
three study variables while on THC. "No response" was
defined as < 30% reduction of at least two study
variables while on THC.
THC PLASMA CONCENTRATIONS
Five-milliliter aliquots of venous blood
were drawn from a heparin lock placed in each patient the
day of chemotherapy. Blood samples were drawn immediately
before each THC or placebo dose and 1 hour later.
Within 6 h after collection in glass tubes,
plasma was drawn off heparinized blood samples and
subsequently stored at - 40 degrees Centigrade. Plasma
samples were quantitatively analyzed for THC by Battelle
Laboratories, Columbus, Ohio. The analysis was done by gas
chromatography/chemical ionization-mass spectrometry (13,
14). Deuterium-labeled THC was used as an internal
standard.
STATISTICAL ANALYSIS
Statistical analyses were restricted to
Phase I of the study. The data were analyzed by three
different methods. The first method, described by Koch
(15), used only data for the first paired trial. This
method tested whether the relative efficacy of THC or
placebo depended on the order of administration in the
first two trials, whether one drug was more effective than
the other, and whether the effectiveness of both drugs
changed from the first trial to the second. In the second
method of analysis, for each study variable and each
patient, the sum of the values of Phase-I paired trials in
which THC was administered was subtracted from the sum of
the Phase-I paired trials in which placebo was
administered. The sign of this difference was ascertained
for each patient and each variable and a sign test done.
The third method of analysis consisted of a blocked
Wilcoxon test for each variable in which the 15 patients
determined the blocks. The data within each block consisted
of the Phase-I paired trials for that patient. All
significance levels correspond to two-tailed tests.
Table 1.
Nausea and vomiting variables in Phase I
(Click
here
to view)
RESULTS
Between August 1977 and September 1978, 19 patients with
osteogenic sarcoma receiving high-dose methotrexate were
approached for entry into the study. Fifteen patients agreed
to participate. None of these patients was deemed ineligible
for the study based on psychiatric evaluations. Four of the
patients were inexperienced users marijuana before entering
the study. The 15 patients completed a total of 97 drug
trials in both Phase I and 11 58 THC and 39 placebo trials. A
drug administration compliance rate of 96% was maintained
throughout the study.
PHASE I
Table 1 lists the results of the 64 completed paired
trials in Phase I. Each study variable represents the sum of
all responses on THC trials and placebo trials completed by
each patient. There was a reduction of nausea and vomiting in
14 of 15 patients. Eight of the 15 patients had an
"excellent" response, specifically a > 80% reduction of
all nausea and vomiting variables, while on THC. Six of the
IS patients had a "fair" response to THC, namely a > 30%
but < 80% reduction of at least three study variables. All
four inexperienced marijuana users were "excellent"
responders to THC.
Using the method of Koch (15) to analyze the first two
trials, THC was found to be of statistically significant
benefit for the number of vomiting and retching episodes (p
< 0.02), degree of nausea (p < 0.01), duration of
nausea (p < 0.01), and volume of emesis (p < 0.01). The
difference for volume of oral intake approached, but did not
achieve, statistical significance. For none of these
variables was there any indication that response to THC and
placebo changed uniformly between the first and second
trials. For the degree of nausea score, however, the relative
efficacy of THC did significantly differ depending upon the
order of administration (p < 0.05). The relative efficacy
of THC in reducing the degree of nausea score was greater for
Trial I than for Trial 2. For Trial 1 alone, THC was
significantly better than placebo with regard to degree of
nausea (p < 0.01). However, for Trial 2 the difference was
not statistically significant. The results of the other two
statistical tests applied were very similar to each other.
With either of these tests THC was significantly better than
placebo with regard to number of episodes of vomiting and
retching, degree of nausea, duration of nausea, and volume of
emesis (p < 0.001). With both tests, the differences in
volume of oral intake between THC and placebo did not
approach statistical significance.
Plasma concentrations from 18 THC trials along with the
paired placebo trials were analyzed in 14 patients. To
examine plasma concentrations each trial was divided into
five 3-h time intervals beginning at each drug
administration. Table 2 summarizes the plasma concentration
determinations after oral and smoked THC doses. In placebo
trials, where the plasma concentrations were 0 ng/ mL,
patients experienced nausea or vomiting, or both, in 65 of 90
time intervals, an incidence of 72%. On THC trials, plasma
concentrations of < 5.0 ng/mL, 5.0 to 10.0 ng/mL, and >
10.0 ng/mL were associated with incidences of nausea or
vomiting, or both, of 44%, 21%, and 6%, respectively. The
incidence of nausea and vomiting decreased with elevation of
THC plasma concentrations. It might be argued that the
association of THC plasma concentrations to the incidence of
nausea and vomiting is not causally related to an antiemetic
effect of THC, but rather due to increased absorption of oral
doses by the gastrointestinal tract in patients experiencing
less nausea and vomiting from other causes. To address this
issue, we examined plasma concentrations measured after
smoked THC and placebo doses. Patients who vomited during the
course of a trial were requested to smoke their remaining
doses. The incidence of nausea and vomiting after the
administration of placebo cigarettes was 96%. Smoked THC
cigarettes resulting in plasma concentrations of < 5.0,
5.0 to 10.0 and > 10.0 ng/mL were associated with
incidences of nausea and vomiting of 83%, 38%, and 0%,
respectively. All of the patients who smoked their THC doses
were experienced cigarette smokers. We concluded that
elevations of THC plasma concentrations, achieved primarily
by the inhalation route, also resulted in a reduced incidence
of nausea and vomiting.
Table
2. Delta-9-Tetrahydrocannabinol (THC) Plasma
Concentrations Compared to Incidence of Nausea and Vomiting
(Click
here
to view)
Table
3. Oral Versus Delta-9-Tetrahydrocannabinol (THC)
Absorption (Click
here
to view)
Despite a constant dose of THC given for each drug
administration, absorption via the oral and inhalation routes
was not uniform between patients or for individual patients.
Thirty-one of 70 (44%) oral doses resulted in TI-IC plasma
concentrations > 5.0 ng/mL I h after administration, with
a range of 0 to 26.6 ng/mL. Table 3 lists the mean plasma
concentrations achieved 1 h after oral and smoked doses from
18 THC trials. Oral absorption was greatest for the first two
doses, with mean 1 h plasma concentrations of 7.1 and 6.4
ng/mL. Subsequent oral doses resulted in mean 1 h plasma
concentrations of 4.3, 4.7, and 4.5 ng/mL. Mean 3-h plasma
concentrations were consistently lower than mean 1 h values
measured after oral and smoked doses. Variable absorption is
suggested by the large standard deviations associated with
each of the mean plasma concentrations.
The inhalation route was more reliable in achieving
adequate blood concentrations: 12 of 17 smoked doses
resulted in plasma concentrations > 5 ng/mL 1 h after
smoking, with a range of 0 to 13.6 ng/mL. In three of four
scheduled doses, smoked THC resulted in greater mean plasma
concentrations than did oral THC, with values of 7.8, 7.5,
7.1 ng/mL. There was no evidence of plasma accumulation of
THC with repeated administration every 3 h.
Table
4. Subjective "High" Compared to Incidence of Nausea
and Vomiting (Click
here
to view)
Patients were asked to rate the magnitude of their
psychological "high" on a 0-3 scale: 0 = none; I = slightly;
2 = moderately; 3 = greatly. Using time intervals similar to
those employed to analyze the plasma concentrations, the
patients' subjective "high" rating can be compared with the
incidence of nausea or vomiting, or both. Table 4 lists the
comparative results of the subjective "high" ratings with the
incidence of nausea or vomiting, or both, in all THC trials
of Phase I. In those time intervals in which patients rated
their "highs" as 0 or I, the incidence of nausea or vomiting
was 46%. For "high" ratings of 2 and 3 the incidence of
nausea or vomiting decreased to 33% and 18%, respectively.
Therefore, the greater magnitude of the subjective "high"
appeared to be associated with a decreased incidence of
nausea or vomiting.
The subjective rating of comfort was recorded by each
patient during each wakeful hour of the observation period.
The patient was asked to rate comfort by choosing the
following: very comfortable (2); somewhat comfortable (1);
somewhat uncomfortable (-- I); and very uncomfortable (-- 2).
By summing the numerical scores associated with each response
and dividing by the total number of responses, a mean comfort
rating could be determined for all wakeful hours on THC and
placebo trials for each patient. Figure 1 shows the mean
comfort rating for all 15 patients on placebo and THC trials.
All 14 patients who had a reduction of nausea and vomiting on
THC also had an increase in their mean comfort rating. The
one nonresponder patient had a decrease in comfort on THC
compared to placebo.
[Webmaster note: Figure 1 involves more than tables and
would not accurately scan into the computer with Textbridge
Pro. The caption under Figure 1 states: Mean subjective
comfort rating of 15 patients on placebo versus
delta-9-tetrahydrocannabinol (D -9-THC) trials. Each line
represents one patient. All patients who had a reduction in
nausea and vomiting on THC also had an increase in their
mean comfort rating. The one nonresponder patient had a
decrease in comfort rating on THC compared to placebo. See
page 823 in the original article.]
SIDE EFFECTS
A common side effect of THC was sedation. When reviewing
the patients' subjective responses during all of the trials,
12 of 15 patients rated themselves sleepier per hour on THC
than on placebo. Short-lasting episodes of tachycardia in the
range of 100 to 120 beats/mm and dizziness associated with
orthostatic changes were occasionally noted. These episodes
were well tolerated and required no specific medical
intervention. Five dysphoric reactions occurred out of a
total of 281 THC drug doses (2%). These reactions occurred in
four patients, three of whom were experienced marijuana
users. The reactions manifested themselves as short-lasting
episodes (about 30 minutes) of anxiety (one patient),
disorientation (one), paranoia (one), and depression (two
patients). No other intervention besides reassurance of the
patient was necessary to treat these adverse reactions.
OTHER OBSERVATIONS
Four "excellent" responders to THC have entered Phase II
of the study. In contrast to Phase I, all four patients had
only "fair" responses to repeated THC trials. Patient 4, for
example, had almost complete elimination of nausea and
vomiting while on THC during Phase I (see Table 1). In Phase
II this patient completed an additional 12 trials (10 THC,
two placebo) and had a 50% reduction in nausea and vomiting
as determined by comparison of the average values of each
study variable for the THC and placebo trials. Two patients
entered Phase II of the study as "fair" responders to THC.
These patients became nonresponders to THC despite an
increased dose in accordance with the study protocol.
Five patients with resections of soft tissue sarcomas
receiving monthly adjuvant doxorubicin and cyclophosphamide
chemotherapy were also studied. Doxorubicin and
cyclophosphamide were given at a constant dose of 70 and 700
mg/m2, respectively. These patients were studied in the same
manner as patients in Phase I who received high-dose
methotrexate. Three of the patients have been nonresponders
to THC and two, "fair" responders.
DISCUSSION
We have found that a combination of oral and smoked THC is
a highly effective antiemetic compared to placebo in patients
receiving high-dose methotrexate chemotherapy. This report
confirms and extends earlier observations reported by Sallan
and associates (7), who found oral THC to be an effective
antiemetic in patients receiving various chemotherapeutic
agents (7).
In addition, it appears that the antiemetic effect of THC
is associated with the THC plasma concentration after oral
and smoked doses. When compared with placebo, the
incidence of nausea and vomiting was reduced to one third
when THC plasma concentrations of 5.0 to 10.0 ng/mL were
measured and to one tenth with THC plasma concentrations >
10.0 ng/mL. Similarly, elevations of THC plasma
concentrations achieved primarily by the inhalation route
were also associated with reductions in the incidence of
nausea and vomiting. These data pertain only to patients
receiving high-dose methotrexate at a dose of 250 mg/kg.
Preliminary data indicate that the antiemetic effect of THC
in patients receiving a combination of doxorubicin and
cyclophosphamide may be less effective.
In our patients, as has previously been reported, oral
doses administration of THC was associated with variable
absorption from the gastrointestinal tract (16). Oral
doses administered throughout the day resulted in a wide
range of plasma concentrations between patients as well as
for individual patients. Only 44% of the oral doses achieved
plasma concentration > 5.0 ng/mL 1 h after drug
administrations. Sallan and co-workers (7) considered
inadequate drug absorption as a possible contributing factor
to the lack of an antiemetic response seen in some patients.
We concur, since THC plasma concentrations appeared to be
causally related to an antiemetic response in our study. To
avoid this problem, we switched patients to the inhalation
route of drug administration when vomiting occurred. Inhaled
marijuana results in the same psychological effects as orally
administered THC (17).
In our patient populations, smoked THC was more reliable
than oral THC in achieving therapeutic blood
concentrations. About 71% of the inhaled doses of THC
resulted in plasma concentrations > 5.0 ng/mL I h after
drug administration. Since all of our patients who smoked THC
were experienced cigarette smokers, we could not determine
whether nonsmokers would have absorbed inhaled doses
differently. Although the inhalation method of THC
administration avoids the ineffective route of oral drug
administration in a nauseated or vomiting patient, it has
some drawbacks in patient acceptability. Many patients
complained of the adverse taste of smoked marijuana, which
induced nausea and vomiting in a few instances. Also,
patients who are nonsmokers may not be willing or able to
smoke THC. Clearly, an alternative parenteral drug route
needs to be established if THC is to have wide clinical
acceptability.
In Phase II there was diminished effectiveness of THC as
an antiemetic with repeated drug trials. Some reduction in
THC effectiveness may be attributable to the normal variation
of nausea and vomiting responses in a patient observed for
multiple courses and to the fact that only THC responders
were studied in Phase II. The very minimal course-to-course
variation observed in Phase I for "excellent" responders
would not, however, seem to account entirely for the reduced
responses. McMillan and colleagues (18) have demonstrated in
animals that infrequent doses of THC can result in tolerance,
and this may account for our observations. Another possible
factor is the development of anticipatory or conditioned
nausea arid vomiting, which commonly occurs in patients
receiving repeated courses of chemotherapy. Such patients,
when exposed to treatment-related stimuli, become nauseated
even before chemotherapy. The presence of anticipatory nausea
or vomiting may make a patient more refractory to an
antiemetic. Three of the six patients in Phase II developed
these anticipatory responses as determined by questionnaires
completed by every patient the day before each chemotherapy
session. Our study was not designed to assess the ability of
THC to prevent or reduce anticipatory nausea or vomiting.
The sedative effect of THC was documented in 80% of our
patients. Sedation has been reported to be the commonest side
effect of phenothiazine antiemetics as well (19). Moertel and
Reitemeier (4) examined this side effect when comparing
various phenothiazines as antiemetics. In their study, a
sodium pentobarbital control was not any different from an
inert placebo control in relieving nausea and vomiting
induced by fluoruracil. Although the mechanism of THC's
antiemetic effect is unknown, it would be unlikely to be due
solely to its sedative properties.
Appetite stimulation has been reported after the smoking
of marijuana (20, 21). To assess appetite, oral intake during
each drug trial was measured. Oral intake on THC trials did
not differ from that on placebo trials. The concomitant
infusion of a chemotherapeutic drug may have precluded any
appetite-enhancing actions of THC in our patient
population.
Nabilone, a synthetic cannabinoid with minimal euphoriant
effects capable of being administered parenterally, has been
reported to have antiemetic properties in patients receiving
chemotherapy (8, 9, 11). Unfortunately, additional data have
indicated long-term animal toxicity that may preclude its
clinical usefulness (11). At present, no available agents
exist to substantially alleviate the nausea and vomiting
associated with chemotherapy. Our data show that oral or
smoked THC is an effective antiemetic in patients receiving
high-dose methotrexate chemotherapy. The antiemetic action
appears to be related to THC plasma concentrations as well as
to the patient's psychological "high." A dose schedule of 10
mg/in2 every 3 h for a total of five doses was associated
with substantial therapeutic benefit and minimal
toxicity.
Additional studies relating to THC drug tolerance,
effectiveness against nausea and vomiting produced by other
chemotherapy regimens, and comparisons with conventional
antiemetics need to be done.
ACKNOWLEDGMENTS
The authors thank the nursing staff of the National
Institutes of Health Clinical Center 10 East ward for
carefully collecting the clinical data; and Dr. Roger Foltz
and Mr. Bruce Hidy for doing the delta-9-tetrahydrocannibinol
plasma determinations.
Requests For reprints should be addressed to Alfred E.
Chang, M.D.; Surgery Branch, National Cancer Institute,
Building 10, Room 10N116; Bethesda, MD 20205.
Received 4 May 1979, revision accepted 29 August 1979.
REFERENCES
1. HARRIS JG. Nausea, vomiting and cancer treatment. CA.
1978; 28:1 94-201.
2. WHITEHEAD VM. Cancer treatment needs better
antiemetics. N Engl J Med. t975; 293:199-200. Letter.
3. MOERTEL CG, RETTEMElER RJ, GAGE RP. A controlled
clinical evaluation of antiemetic drugs. JAMA. 1963;
186:116-8.
4. MOERTEL CG, REITEMETER RJ. Controlled clinical studies
of orally administered antiemetic drugs. Gastroenterology.
1969; 57:262-8.
5. MOERTEL CG, SCHUTT AJ, HAHN RG, OFALLON JR. Oral
benzquinamide in the treatment of nausea' and vomiting. Clin
Pharmacol Ther. 1975; 18:554-7.
6. PLOTKIN DA, PLOTKIN D, OKUN R. Haloperidol in the
treatment of nausea and vomiting due to cytotoxic drug
administration. Curr Ther Res Gun Exp. 1973; 15:599-602.
7. SALLAN SE, ZINBERO NE, FREI E III. Antiemetic effect of
della-9-tet-rahydrocannabinol in patients receiving cancer
chemotherapy. N Engl J Med. 1975; 293:795-7.
8. HERMAN TS, JONES SE. DEAN J, et at. Nabilone: a potent
antiemetic cannabinol with minimal euphoria. Biomedicine
[Express] 1977; 27:331-4.
9. NAGY CM, FURNES BE, ElNHORN LH, BOND WH. Nabilone
antiemetic crossover study in cancer chemotherapy patients.
Proc Am Assoc Cancer Res-Am Soc Clin Oncol. 1978; 19:30.
Abstract.
10. ISRAEL L, RODARY C. Treatment of nausea and vomiting
related to anticancerous multiple combination chemotherapy:
results of two controlled studies. J Int Med Res. 1978;
6:235-40.
11. 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.
12. STILLMAN R, GALANTER M, LEMBERGEJS L, Fox 5,
WEINGARTNER H, WYATT RJ. Tetrahydrocannabinol (THC):
metabolism and subjective effects. Life Sci1976:
19:569-76.
13. ETRICH R, FOLTZ RL. Quantitation of
delta-9-tetrahydrocannabinol in body fluids by gas
chromatography/chemical ionization-mass spectrometry:
cannabinoid assays in humans. Natl Inst Drug Abuse Monogr.
1976; 7:88-95.
14. FOLTZ RL, CLARKE PA, HIDY BJ, LIN DCK, GRAFFEO AP,
PETERSON BA. Quantitation of delta 9-tetrahydrocannabinol and
11-Nor-delta-9-tetrahydrocannabinoI-9-carboxylic acid in body
fluids by GC/CI-MS. In: VINSON JA, ed. Cannabinoid Analysis
in Physiological Fluids. Washington, D.C.: ACS; 1979; 59-72.
(ACS symposium Series 98).
15. KOCH GG. The use of non-parametric methods in the
statistical analysis of the two-period change-over design.
Biometrics. 1972; 28:577-84.
16. PEREZ-REYE5 M, LlPTON MA, TIMMONS MC, WALL ME, BRINE
DR, DAVIS KR. Pharmacology of orally administered
della-9-tetrahydro-cannabinol. Clin Pharmacol Ther. 1973;
14:48-55.
17. LEMBERGER L, WEISS JL, WATANABE AM, GALANTER IM, WYATT
RJ, CAROON PV. Delta-9-tetrahydrocannabinol temporal
correlation of the psychologic effects and blood levels after
various routes of administration N Engl J Med.
1972:286:685-S.
18. McMILLAN DE, DEWEY WL, HARRIS LS. Characteristics of
tetrahydrocannabinol tolerance. Ann NY Acad Sci. 1971;
91:83-99.
19. CLARKE RSJ, DUNDEE JW. Side effects of antiemetics:
results of a class experiment. Eur J Pharmacol.
1971:14:291-300.
20. HOLLISTER LE. Hunger and appetite after single doses
of marijuana, alcohol, and dextroamphetamine. Clin Pharmacol
Ther. 1971; 12:44-9.
21. REGELSON W, BUTLER JR. SHULTZ J, KIRK T, PECK L, GREEN
ML. Delta-9-tetrahydrocannabinol as an effective
antidepressant and appetite-stimulating agent in advanced
cancer patients. In: BRAUDE MC, SZARA S, eds. The
Pharmacology of Marihuana. New York: Raven Press:
1975:763.
December 1979 · Annals of Internal Medicine
· Volume 91 · Number 6
|
