Lysergide (LSD) is a semi-synthetic hallucinogen and is one of the most potent drugs known. Recreational use became popular between the 1960s to 1980s, but is now less common. During the 1960s, LSD was investigated for a variety of psychiatric indications, including the following: as an aid in the treatment of schizophrenia; as a means of creating a "model psychosis"; as a direct antidepressant; and as an adjunct to psychotherapy. LSD is listed in Schedule I of the United Nations 1971 Convention on Psychotropic Substances. LSD possesses a complex pharmacological profile that includes direct activation of serotonin, dopamine and norepinephrine receptors. In addition, one of its chief sites of action is that of compound-specific (“allosteric”) alterations in secondary messengers associated with 5HT2A and 5HT2C receptor activation and changes in gene expression. The hallucinogenic effects of LSD are likely due to agonism at 5HT2A and 5HT2C receptors. LSD is also an agonist at the majority of known serotonin receptors, including 5HT1A, 5HT1B, 5HT1D, 5HT5A, 5HT6 and 5HT7 receptors. L-Lysergide (L-LSD) is a non-psychoactive enantiomer of LSD. D-LSD not only completely eradicated the response to 10 muM dopamine in rat hippocampus preparations but also consistently stimulated adenylate cyclase activity. L-LSD (80 muM) was without effect. Also both D- and L-LSD bind to solubilized 5-HT1 sites with comparable high affinities, whereas D-LSD has a markedly higher affinity for the membrane 5-HT1 site. In crude bovine frontal cortical membranes, D-LSD has high affinity for the 5-HT 1 binding site (IC50 = 40 nM), while L-LSD has the very low affinity (IC50 = 10,000 nM versus [3H]5-HT). Solubilized 5-HT1 sites retain high affinity for D-LSD binding site (IC50 = 75 nM). However, L-LSD also has a high affinity for the soluble binding site (IC50 of 200 nM). Thus while the membrane-bound binding site strongly differentiates between D- and L-LSD, both stereoisomers bind to the soluble binding site with relatively high affinity. Lovell and Freedman have suggested that the lone-pair electrons on the 3 nitrogen atoms in D-LSD are oriented downward from the plane of the molecule and form a tripod of electron donor pairs which interact with the 5-HT 1 binding site. This area of attachment of D-LSD would be expected to be much larger than the area of attachment of 5-HT to the binding site, and to overlap or encompass the 5- HT binding region. The lower affinity of L-LSD for the membrane binding site would be due to the fact that one or more of the lone-pair electrons is oriented above the plane of the molecule. The diethylamide group of L-LSD would also be oriented differently. It would therefore either be unavailable for interactions with the binding site or its orientation would be a steric hindrance to binding.