Cannabinoids drug tolerance

Pertwee RG. Tolerance to and dependence on psychotropic cannabinoids. In Pratt J, editor. The Biological Basis of Drug Tolerance. London Academic Press, 1991 232-65. Aceto MD, Scates SM, Lowe JA, Martin BR. Dependence on delta 9-tetrahydrocannabinol studies on precipitated and abrupt withdrawal. J Pharmacol Exp Ther 1996 278(3) 1290-5. 

Pertwee RG. Tolerance to and dependence on psychotropic cannabinoids. In Pratt J, editor. The Biological Basis of Drug Tolerance. London Academic Press, 1991 232-65. 

Welburn PJ, Starmer GA, Chesher GB, Jackson DM. (1976). Effect of cannabinoids on the abdominal constriction response in mice within cannabinoid interactions. Psychopharmacoiogia. 46(1) 83-85. Welch SP. (1997). Characterization of anandamide-induced tolerance comparison to delta 9-THC-induced interactions with dynorphinergic systems. Drug Aicohoi Depend. 45(1-2) 39-45. 

A9-Tetrahydrocannabinol is the major psychoactive cannabinoid in marijuana (Cannabis sativa). Its synthetic form, dronabinol, became available in the U.S. in 1985 as an antiemetic for patients receiving emetogenic chemotherapy. However, it is seldom used as a first-line antiemetic because of its psychoactive effects, and its use is usually limited to patients who have a low tolerance or minimal response to other antiemetic drugs (see Chapter 18). 

Tetrahydrocannabinol is metabolized in the liver to form active metabolites which are further metabolized to inactive polar compounds these are excreted in the urine. Some metabolites are excreted into the bile and then recycled via the enterohepatic circulation. Because of their high lipophilicity, most active metabolites are widely distributed in fat deposits and the brain, from which sources they are only slowly eliminated. The half-life of elimination for many of the active metabolites has been calculated to be approximately 30 hours. Accordingly, accumulation occurs with regular, chronic dosing. Traces of the cannabinoids can be detected in the blood and urine of users for many days after the last administration. There is some evidence of metabolic tolerance occurring after chronic use of the drug. THC and related cannabinoids readily penetrate the placental barrier and may possibly detrimentally affect foetal development. 

Gonzalez, S., Fernandez-Ruiz, J., Di Marzo, V., Hernandez, M., Arevalo, C., Nicanor, C., Cascio, M.G., Ambrosio, E., and Ramos, J.A. (2004) Behavioral and molecular changes elicited by acute administration of SR141716 to delta-9-tetrahydrocannabinol-tolerant rats an experimental model of cannabinoid abstinence. Drug Alcohol Depend 10 159-170. 

Smith CG, Almirez RG, Scher PM, Asch RH. 1984. Tolerance to the reproductive effects of A -tetrahydro-cannabinol. Comparison of the acute, short-term, and drug chronic effects on menstrual cycle hormones, in Agurell S, Dewey W, Willette R., Eds. The Cannabinoids Chemical, Pharmacologic and Therapeutic Aspects. New York Academic Press, pp. 471 485. 

Acute and chronic administration of alcohol can inhibit the biotransformation or detoxification of many drugs, such as barbiturates, meprobamate, and amphetamines by liver enzymes. The effect can occur in two opposite ways. Alcohol and cannabinoids effects are additive. Both are CNS depressants. Animal studies indicate that simultaneous administration of alcohol and tetrahydrocannabinol (THC), the psychoactive component of marijuana, increased the tolerance and physical dependence to alcohol. Human studies show that alcohol and THC combination enhanced the impairment of physical and mental performance only, and there is no evidence of any interaction between both drugs. With barbiturates. 

The lOM report describes the effect of THC, the primary psychoactive ingredient in marijuana cannabinoids, which are the compounds related to THC and marijuana, the unpurified plant substances. The lOM report studied the effects of isolated cannabioids and concluded that they have a natural role in pain modulation, control of movement, and memory. The role on cannabioids in the immune system was unclear and the report concluded that the brain develops tolerance to cannabioids. While animal research demonstrated dependence on cannabioids, the potential for dependence was seen as occurring under a more narrow range of conditions than for drugs such as minor tranquilizers, opiates, cocaine, or nicotine. Withdrawal symptoms were observed in animal studies but were mild compared to drugs such as minor tranquiflzers or opiates. 

Studies of cannabinoid agonists in acute post-operative pain have been mixed, with nabilone found to actually worsen post-operative pain in one report. However, there is evidence for their use with opioid drugs, adjunctively, for possible synergistic effects or to delay the development of opioid tolerance. 

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