Pharmacol. Biochem. Behav. 49:187-195, 1994. Excerpts from:

Cannabinoids and Appetite Stimulation

by Richard D. Mattes, Karl Engelman, Leslie M. Shaw and Mahmoud A. Elsohly

Research conducted in Philadelphia, PA and sponsored by the Federal Government.

Summary of conclusions: ...the present data demonstrate an appetite-stimulating action of THC in healthy, adult, light marijuana users only when administered at a dose of 2.5 mg b.i.d. by rectal suppository. Comparable oral dosing was less effective. Acute administration of the drug by various routes at levels often used to control nausea and emesis did not elicit an increment in energy intake. Under the conditions of these studies, subject age, gender, hunger status, reported "high," and plasma drug level were not significantly associated with drug effects on food intake. However, different results may be obtained under varying conditions (i.e., a social setting conducive to positive drug-related effects on psychological and behavioral measures) or with selected clinical populations.

Method--Study Protocols (4)
Data are presented from four studies, all of which had within-subject designs. The first was a double-blind, placebo-controlled, single oral dose study involving an age and gender stratified study population (acute oral study). In the second, subjects were monitored after single oral, sublingual, and smoked doses (multiroute study). The third involved administration of the THC either PO or PR b.i.d. for 3-day periods (chronic study), and a fourth assessed food intake following single oral dosing of subjects in fasted and fed states (satiety study). Different individuals were enrolled in each study. All subjects were recruited by public advertisements and received monetary compensation for their participation. Subjects were informed that each study's aim was to document the physiological actions of the drug; dietary effects were never mentioned. The studies were approved by the Committee on Studies Involving Human Beings at the University of Pennsylvania.

1. Acute Oral Study
This study was designed to determine whether ingestion of the currently FDA-approved formulation of THC stimulates energy intake and alters the type, nutrient composition, or taste properties of selected foods.

Protocol. Participants reported to the hospital at 0800 h after an overnight fast. Vital signs were collected, a dietary questionnaire was completed, and a battery of chemosensory tests (described elsewhere (27)) was administered. A standard breakfast (421 kcal) comprised of one buttered (5 g) English muffin (57 g), orange juice (240 ml), and 2% milk (240 ml) was consumed in its entirety. Immediately afterwards, a single dose (15 mg for males, 10 mg for females) of delta-9-THC in sesame oil (Marinol, Unimed, Inc, Somerville, NJ) or matched placebo was swallowed. At 1000 h a tray of pre-weighed foods (sandwhich cookies, cupcakes, chocolate candies, bananas, red apples, pudding, carrots, fruit punch, potato chips, corn chips, peanuts, cheese, crackers, dill pickles, V-8 juice, plain yogurt, green apple, sour hard candies, grapefruit, cranberry juice, bittersweet chocolate, radishes, walnuts, celery, raw broccoli, orange marmalade, bitter lemon drink) was made available for the rest of the test day. This array of foods provided options that were rated by other subjects in previous studies as primarily sweet, sour salty, or bitter. Vital signs were taken and the dietary questinnaire was completed at this time and hourly for the duration to the day. Sensory testing and blood draws were repeated at 1100, 1300, and 1500 h. Lunch was self-selected from a menu containing about 60 items plus condiments at 1100 h and the preweighed items were were presented at 1200 h. Between scheduled activities, subjects were free to engage in quiet recreational activities on the hospital floor. Only one subject was tested per day. Following subject release (at approximately 1800 h), all foods were reweighed to determine the amounts consumed (i.e., no food was given to the other patients or hoarded for later consumption). A minimum of 3 weeks was interposed between sessions to ensure that any drug administered during a study day was cleared before subsequent testing.

2. Multiroute study
This study explored the acute appetite stimulating effects of THC following different routes of administration.

The testing protocol was identical to that used in the acute oral study except multiple routes of drug delivery were tested. After breakfast, a single dose (15 mg for males, 10 mg for females) of delta-9-THC in sesame oil (Marinol, Unimed, Inc, Somerville, NJ) was swallowed, allowed to dissolve under the tongue or a single710-795 mg marijuana cigarette (2.57 +/- 0.06% delta-9-THC) was smoked (supplied by the National Institute on Drug Abuse, Research Triangle Park, NC). Smoking entailed inhaling for 3 s, holding 12 s, exhaling, waiting 15 s and repeating until the cigarette was burned down to a 2 cm stub. Each test session was separated by at least 3 weeks. Because of concern about lingering drug effects on behavior, subjects remained in the hospital until 2300 h. The snack tray was available until 2000 h. Subjects were provided a self-selected dinner at 1800 h (the nutrient content of which was measured).

3. Chronic Study
This study was designed to provide preliminary data on the appetite stimulating effects of THC following repeated low (2.5 mg) doses by two (oral and rectal suppository) routes.

Protocol. The types of measures assessed (e.g., sensory function, blood pressure, salivary function) were identical to those monitored in the acute oral study, but the timing of the activities differed. Blood was drawn at 0800, 1200, 1600, 2000, and 2300 h each day. Sensory testing was conducted at 0800 and 1600 h the first day and only at 1600 h on the subsequent two days. Eating opportunities included a self-selected breakfast (0800 h), lunch (1200 h), dinner (1730 h), and a snack tray (1000-2300 h) each day. A 2.5 mg dose of delta-9-THC was administered PO or PR (as the hemisuccinate ester, supplied by ElSohly Laboratories, Oxford, MS) at 0900 and 1700 h. The two 3-day test sessions were separated by a minimum of 3 weeks.

4. Satiety Study
In this study,the appetitive effects of THC administration to subjects in a fed and fasted state were contrasted to determine whether the drug alters satiety. Failure to compensate for the energy provided by the pretreatment breakfast would indicate a disruption of satiety mechanisms.

Protocol. The testing protocol was identical to that used in the oral study except subjects either received no morning meal or one containing 455 kcal comprised of scambled eggs (87.3 g), bacon (14.3 g), half of an English muffin (28 g) with 7.5 g of margarine, orange juice (120 cc), and milk (240 cc of whole milk). Immediately after breakfast, a single dose (15 mg for males, 10 mg for females) of delta-9-THC in sesame oil (Marinol, Unimed, Inc, Somerville NJ) was swallowed. The 2 test days were separated by a minimum of 3 weeks.

Selected Results/Discussion

...There was a high level of variability in plasma drug levels,especially among subjects after oral drug administration coincident with a small standard breakfast.

...Snacks accounted for more energy than the self-selected lunch during both active and placebo treatments.

...Intakes were also similar following acute administration of the drug by oral, inhaled, and sublingual routes.

...Two of the subjects who reported experiencing a pronounced "high" 2 h following inhalation of THC elected to sleep through lunch and had the lowest daily intakes (830 and 482 kcal). Omitting these subjects, mean energy intake after inhalation of THC was 2719 +/- 359 kcal; 481 kcal more than oral dosing and 603 kcal greater than sublingual dosing effects. Due to the high variance and small sample size, these difference were not statistically significant.

...Snack items (e.g., sweet pastries, chocolate candy) were consistently the largest contributors of energy.

...Energy intake was not significantly related to reported "high" under any condition. However, it should be noted that approximately 20% of participants in the acute oral study who reported little of no "high" during the study day volunteered information that they experienced a "high" later that evening and ate large amounts of food.

...Analyses used intake scores computed as the difference between active and placebo treatment days. No significant association was observed between age and difference in total energy intake (r = 0.11), reported "high" (r = -0.11), AUC for parent drug (r = 0.02), or AUC for metabolite levels (r = -0.06).

...Inhalation of THC led to more consistent elevations of plasma drug concentration and tended, albeit not significantly, to promote intake.

...Anectodal reports indicate that marijuan may also alter eating patters and, in particular, stimulate a desire for sweet items (12, 15, 20, 21). More frequent intake of snack foods accounted for much of the noted increase in total energy intake in several controlled studies (12, 13, 15).

...Drug-induced behavioral changes resulting in decreased energy expenditure have been hypothesized to account for increased energy intake (39). Shifts of fluid balance do not account for the findings (17, 39). Thus, our failure to document a THC-related increment in food intake should not be interpreted as evidence that THC will be ineffective in the maintenance of adequate body weight in clinical populations.

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