Tolerance cannabinoids

Teesson M, Lynskey M, Manor B, et al The psychometric properties of BSM-IV cannabis use disorders. Brug Alcohol Bepend 68 235—262, 2002 Tsou K, Patrick SL, Walker JM. Physical withdrawal in rats tolerant to delta 9-tetrahydrocannabinol precipitated by a cannabinoid receptor antagonist. Eur J Pharmacol 280 R13-R15, 1995... 

Chronic exposure to THC causes a regulation of cannabinoid receptors, which appears to be region-specific (Zhuang et al. 1998). For example, while increases in cannabinoid receptor mRNA are seen in the cerebellum and hippocampus at 7 and 14 days of chronic treatment, decreases were seen in the striatum from days 2 to 14. However, levels returned to normal in all the regions by day 21, which coincides with reports of behavioral tolerance. 

Conversely, food intake and body weight are reduced by the selective cannabinoid CBl antagonist SR 141716. Tolerance developed to the anorectic effect of SR 141716 within 5 days of chronic treatment, but body weight remained low throughout 14 days of treatment. In contrast, chronic THC treatment (15 days) suppresses intake of food and water (Drewnowski and Grinker 1978). This effect is of short duration, with... 

A rapid tolerance to the acute effects of THC occurs in mice, which rapidly reverses as well (Hutcheson et al. 1998). Although chronic exposure to THC alters cannabinoid receptors, this effect is not irreversible (Westlake et al. 1991). 

THC is effective in several chemotherapy regimens, including methotrexate and the doxorubicin/cyclophosphamide/fluorouracil combination. Cisplatin treatment, however, is more resistant. Side effects of THC are generally well tolerated, and use may be limited in the elderly or with higher doses. Nabilone is a synthetic cannabinoid that is more effective than prochlorperazine in chemotherapy-induced emesis, including cisplatin. Its side effects are similar to THC. Levonantradol is another synthetic cannabinoid with antiemetic effects, and may be administered orally or intramuscularly. The side effect of dysphoria may limit its use. 

Different cannabinoids have different effects on seizures. Cannabidiol may have the most therapeutic potential of the cannibinoids (Turkanis et al. 1979). Unlike THC, cannabidiol does not have excitatory effects and instead elevates the afterdischarge threshold. Similar to ethosuximide, it decreased the duration and amplitude of afterdischarges. Cannabidiol also lacks the CNS excitatory effects that THC produces. Lesser tolerance is observed with cannabidiol than other cannabinoids (Karler and Turkanis 1981). 

The effects of cannabis on seizures is, at best, unpredictable. Although some cannabinoids have antiseizure effects, tolerance rapidly develops. Further, rebound hyperexcitability following THC administration may render these benefits impractical. Indeed, cannabinoids facilitate seizures and kindling in many studies. Certain isolated cannabinoids may eventually prove useful for treating seizures, but cannabis as a whole is not effective. In light of this, individuals with epilepsy are strongly recommended to avoid cannabis. 

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. 

Martin BR, Sim-Selley LJ, Selley DE. Signaling pathways involved in the development of cannabinoid tolerance. Trends Pharmacol Sci 2004 25 325-30. 

Brain cannabinoid receptor. In humans, psychoactive cannabinoids produce euphoria, enhancement of sensory perception, tachycardia, antinociception, difficulties in concentration, and impairment of memory. The cognitive deficiencies persist after withdrawal. The toxicity of cannabis has been underestimated for a long time, since recent findings revealed that A-9-THG-induced cell death with shrinkage of neurons and DNA fragmentation in the hippocampus. The acute effects of cannabinoids, as well as the development of tolerance, are mediated by G protein-coupled cannabinoid receptors. The CBl receptor and its splice variant, CBl A, are found predominantly in the brain with highest densities in the hippocampus, cerebellum, and striatum. The CB2 receptor is found predominantly in the spleen and in hemopoi-... 

Acute cannabinoid exposure antagonized the amphetamine-induced dose-dependent increase in locomotion, exploration, and the decrease in inactivity. Chronic treatment with (-)-A-9-THC resulted in toler-... 

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. 

Cross-tolerance occurs between THC and alcohol, at least in animal studies, but this does not appear to occur between the cannabinoids and the psychotomimetics. 

Structurally there is little in common between A9-THC and anandamide. The cannabinoids are terpenophenols, while the anandamides are fatty acid derivatives. Yet, pharmacologically they have much in common. Both A9-THC and anandamide were shown to cause a typical tetrad of behavioural actions hypothermia, hypomotility, antinociception and catalepsy. In most behavioural tests, anandamide is somewhat less potent than d9-THC [35, 36]. Repeated injections of anandamide (i.p.) produced tolerance to a challenge with THC or anandamide. This tolerance however was less persistent than that commonly seen with THC, lasting for only one week [37],... 

Lichtman and Martin have shown that cannabinoid-induced antinociception has both spinal and supraspinal components [152]. A spinal a2-noradre-nergic mechanism is involved in cannabinoid antinociception as yohimbine and/or methysergide altered z)9-THC induced antinociceptive effects in rats [153]. A supraspinal mechanism is also involved as cannabinoid analgesia can be produced in spinally transected rats [152], Both similarities and differences were noted on comparison of the antinociceptive effects produced by anandamide (and the more potent fluroanandamide) and d9-THC [154], Anandamide was cross-tolerant to d9-THC, but in contrast to THC, it did not alter opioid-induced antinociceptive effects nor was its action blocked by a k antagonist. 

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. 

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