The active principle of marihuana, Delta9-tetrahydrocannabinol (Delta9-THC), exerts its pharmacological effects by binding to selective receptors present on the membranes of neurons and other cells. These cannabinoid receptors are normally engaged by a family of lipid mediators, called endocannabinoids, which are thought to participate in the regulation of a diversity of brain functions, including pain, mood, appetite and memory. Marihuana use may lead to adaptive changes in endocannabinoid signaling, and these changes might contribute to effects of marihuana as well as to the establishment of marihuana dependence. In the present article, I outline current views on how endocannabinoid substances are produced, released, and deactivated in the brain. In addition, I review recent progress on the development of pharmacological agents that interfere with endocannabinoid deactivation and discuss their potential utility in the treatment of marihuana dependence and other aspects of drug abuse.

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Abstinence following daily marihuana use can produce a withdrawal syndrome characterized by negative mood (eg irritability, anxiety, misery), muscle pain, chills, and decreased food intake. Two placebo-controlled, within-subject studies investigated the effects of a cannabinoid agonist, delta-9-tetrahydrocannabinol (THC: Study 1), and a mood stabilizer, divalproex (Study 2), on symptoms of marihuana withdrawal. Participants (n=7/study), who were not seeking treatment for their marihuana use, reported smoking 6-10 marihuana cigarettes/day, 6-7 days/week. Study 1 was a 15-day in-patient, 5-day outpatient, 15-day in-patient design. During the in-patient phases, participants took oral THC capsules (0, 10 mg) five times/day, 1 h prior to smoking marihuana (0.00, 3.04% THC). Active and placebo marihuana were smoked on in-patient days 1-8, while only placebo marihuana was smoked on days 9-14, that is, marihuana abstinence. Placebo THC was administered each day, except during one of the abstinence phases (days 9-14), when active THC was given. Mood, psychomotor task performance, food intake, and sleep were measured. Oral THC administered during marihuana abstinence decreased ratings of 'anxious', 'miserable', 'trouble sleeping', 'chills', and marihuana craving, and reversed large decreases in food intake as compared to placebo, while producing no intoxication. Study 2 was a 58-day, outpatient/in-patient design. Participants were maintained on each divalproex dose (0, 1500 mg/day) for 29 days each. Each maintenance condition began with a 14-day outpatient phase for medication induction or clearance and continued with a 15-day in-patient phase. Divalproex decreased marihuana craving during abstinence, yet increased ratings of 'anxious', 'irritable', 'bad effect', and 'tired.' Divalproex worsened performance on psychomotor tasks, and increased food intake regardless of marihuana condition. Thus, oral THC decreased marihuana craving and withdrawal symptoms at a dose that was subjectively indistinguishable from placebo. Divalproex worsened mood and cognitive performance during marihuana abstinence. These data suggest that oral THC, but not divalproex, may be useful in the treatment of marihuana dependence.

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Delta(9)-Tetrahydrocannabinol (the active ingredient of marihuana), as well as endogenous and synthetic cannabinoids, exert many biological functions by activating two types of cannabinoid receptors, CB(1) and CB(2) receptors. CB(1) receptors have been detected on enteric nerves, and pharmacological effects of their activation include gastroprotection, reduction of gastric and intestinal motility and reduction of intestinal secretion. The digestive tract also contains endogenous cannabinoids (i.e., the endocannabinoids anandamide and 2-aracidonylglycerol) and mechanisms for endocannabinoid inactivation (i.e., endocannabinoids uptake and enzymatic degradation). Cannabinoid receptors, endocannabinoids and the proteins involved in endocannabinoids inactivation are collectively referred as the 'endogenous cannabinoid system'. A pharmacological modulation of the endogenous cannabinoid system could provide new therapeutics for the treatment of a number of gastrointestinal diseases, including nausea and vomiting, gastric ulcers, irritable bowel syndrome, Crohn's disease, secretory diarrhoea, paralytic ileus and gastroesophageal reflux disease. Some cannabinoids are already in use clinically, for example, nabilone and delta(9)-tetrahydrocannabinol are used as antiemetics.

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Nabilone is a synthesized crystalline benzopyran that resembles the cannabinols but is not a tetrahydrocannabinol. Oral administration of 0.5 to 2 mg to patients with open-angle glaucoma reduced the intraocular pressure from 10% to 54% with an average of 28%. Administration of a topical ophthalmic nabilone solution (0.1 mg/drop) to both eyes of adult albino rabbits (1.5 to 3.5 kg) lowered the IOP an average of 25%. The peak action of the nabilone administered in this manner was 60 minutes, with a return to normal IOP by 180 minutes. Tolerance developed in rabbits after one week of topical administration.

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A procedure was developed for screening of cannabinoids for their ability to reduce intraocular pressure (IOP) using normal rabbits. Eight animals per group were used for statistical significance of data. A negative control group was used for every screen as well as a positive control with 1.5 mg/kg delta 9-THC given intravenously (I.V.). All compounds were tested by I.V. injection and IOP measurements were taken periodically for 5 hours. Data were analyzed by a computer program which takes into account the change in IOP of the control group. Following this procedure we found that delta 8-THC, delta 9-THC, cannabinol, and nabilone were active while cannabidiol was inactive.

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