The abuse of MDMA and other hallucinogenic drugs continues to be a serious problem that is exacerbated by the recent publication of cookbook chemical syntheses and detailed accounts of the doses used and hallucinogenic effects seen in humans for almost all of the 179 phenethylamine and 53 tryptamine analogs that were synthesized and self-administered by A. T. Shulgin and his associates during more than 30 years. These are disturbing developments that substantially aid and encourage clandestine drug production and may presage a resurgence in hallucinogenic drug abuse. We have begun a program to synthesize and evaluate a number of hallucinogenic agents and their antagonists. We recently developed a practical nonchromatographic chemical synthesis of the 5-HT2A receptor antagonist MDL100,907 that is providing this important research tool. We have studied the discriminative stimulus effects of several of these drugs in order to gain further insight into their 5-HT receptor subtype(s) selectivity and the possible receptor role in certain neuropsychiatric disorders. Our results provide quantitative evidence for the predominant, if not exclusive, role of 5-HT(2A) receptors in the discriminative stimulus effects of DOM, 2C-T-7, and DPT in rhesus monkeys. Delta-9 tetrahydrocannabinol (THC) is the major active principal of marijuana and produces spinal analgesia by potentiation of inhibitory glycine receptors. THC produces its classical central effects by interaction at cannabinoid receptors 1 (CB1). We recently showed that 1 and 5-desoxy THC retain the full potentiation of glycine receptors but do not interact with CB1 suggesting that glycine mediated analgesia can be produced without the central effects induced by CB1. Didesoxycannabidiol had no effect on glycine receptors itself but antagonized the actions of THC at glycine receptors. These findings provide a new lead for novel analgesic drugs that lack psychotomimetic produced by THC.
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