Lsd

http://www.askpat.colostate.edu/HotTopicHallucinogenics.htm

Kd = 6 nM

Oelszner W Jr. Displacement of specific serotonin and lysergic acid diethylamide binding by Ergalgin, a new antiserotonin drug. Acta Biol Med Ger. 1980;39(8-9):897-901.

LSD is not produced naturally by humans. It is synthesized in a laboratory and then ingested or absorbed through the skin. Very small doses are needed to induce a hallucinogenic effect (20-100 micrograms), yet only 1% reaches the brain.1 The half-life of the drug ranges from 3-5 hours.2 LSD is inactivated in the liver and then excreted.

In 1978, LSD researchers seemed to be uncertain about the make-up of the serotonin (5-HT) receptor family. They only had data to indicate the presence of one receptor, and at least 13 variants of the receptor have now been identified.3 Furthermore, serotonin was thought to exert its effect through dopaminergic and adrenergic systems as well. LSD appears to be a specific antagonist to 5-HT-2 receptor and agonists of the 5-HT-1A and 5-HT-1C receptors.4 LSD seems to down-regulate 5-HT-2 receptors and dampen overall serotonin activity.5

There were also discrepancies among the IC50 values, as different research had shown values ranging from 200 to 2000 nm.6,7 Furthermore, the researchers were uncertain of the pharmacological properties of LSD binding to the serotonin receptor. In this paper, they were able to explore some of these properties.

More specifically, the investigators sought to create a system where they could test the effects of LSD on the serotonergic system without the effects of the dopaminergic or adrenergic systems. Also, they wanted to better understand LSD's effects on the serotonin receptor by comparing the potencies of various drugs on selective (H3)LSD binding compared to the high-affinity binding of (H3)serotonin.

1 Diaz, Jaime. How Drugs Influence Behavior: A Neurobehavioral Approach. "Hallucinogens: Drugs that Uniquely Alter Consciousness."

2 FEILDMAN. R., & QUENZER, L. (1984). Fundamentals of Neuropsychopharmacology. (207-258). Sunderland, MA: Sinauer Assc., Inc.

207-258). Sunderland. MA: Sinauer Assc., Inc.

3 Kandel, Schwartz and Jessel. Principles of Neuroscience. 4th ed. McGraw-Hill 2000.

4 Pierce P., and Peroutka S. (1990). Antagonist properties of d-LSD at 5-hydroxytryptamine2 receptors. Neuropsychopharmacology. 3(5-6), 503-508.

5 Diaz, Jaime. How Drugs Influence Behavior: A Neurobehavioral Approach. "Hallucinogens: Drugs that Uniquely Alter Consciousness."

6 Bennett, J. L. & Aghajanian, G. K. (1975) Life Sci. 15, 1935-

1944.

7 Fillion, G. M. B., Rousselle, J.-C., Fillion, M.-P., Beaudoin, D. M.,Goiny, M. R., Deniau, J.-M. & Jacob, J. J. C. (1978) Mol. Pharmacol.

14, 50-59.

Whitaker and Seeman used calf caudate homogenate as the substrate for their studies. They were concerned with measuring the specific binding of tritiated LSD ([3H]LSD) in the presence of a variety of competing ligands. Specific activity was measured by subtracting non-specific activity (measuring hot ligand added after incubation with cold ligand) from total activity (measuring all hot ligand added). Competition assays were performed with and without presence of APS (apomorphine, phentolamine, and spiperone, all potent catecholamine agonists).

The result that the study focused on, seemingly the most significant at the time, was attained while comparing the disocciation of [3H]LSD from receptors under competition from different drugs (Fig.1). Comparing dissociation of the triated compound by dopamine with and without the presence of APS, dopamine had much less potency as a competitive agonist under the presence of APS. A similar result was seen when using norepinephrine as a dissociation agonist. Serotonin, however, was considerably more effective under the presence of APS. All of this evidence points to the effects of LSD being a result of a multiple receptor system, as [3H]LSD binds to catecholamine receptors, as well as serotonin receptors.

A second result that was understated in this particular paper, but would prove to be immensely significant for the study of LSD in the future, was seen when comparing the IC50 of tryptamines