Serotonin and LSD

Aghajanian, G. K. Lakoski, J. M. (1984). Hyperpolarization of serotoninergic neurons by serotonin and LSD studies in brain slices showing increased K+ conductance. Brain Res. 305, 181-5. 

It became known in the same year (1954) that the substance reserpine, derived from the Indian plant Rauxcolfia serpentina, had antipsychotic effects similar to those of chlorpromazine This finding was of interest for two reasons the molecular structure of reserpine has some similarity to that of serotonin and LSD and it was found that reserpine liberates serotonin from presynaptic stores in the CNS and thus produces a short-lived excess supply of functionally available serotonin at the synapse. In the context of a serotonin hypothesis of schizophrenia, it could be postulated that the antipsychotic effect of reserpine was due to its ability to liberate serotonin presynaptically and make it functionally available. However, despite its scientific appeal, the serotonin hypothesis of schizophrenia did not last long because it was in conflict with both psychopathological and pharmacological findings ... 

Minnema, D. J., and Rosecrans, J. A. (1982) Alterations of the discriminative stimulus produced by d-amphetamine and LSD in rats neonatally depleted of serotonin or dopamine. Psychopharmacology, 76 ALL (abstr.). 

A few cases have been reported of exacerbation of HPPD by risperidone (Risperdal) (Abraham and Mamen 1996). The exact reason for this is uncertain, but the fact that risperidone and LSD both act at 5-HT2 receptors is probably causative. Also, two cases have been reported of an exacerbation of HPPD by selective serotonin reuptake inhibitors (Markel et al. 1994). 

By 1980, the time that Hofmann wrote up his experiences, the role of the neuromodulators serotonin and dopamine in controlling conscious states was well established. Hofmann knew from the work of Gaddum and others that LSD blocked serotonin and enhanced dopamine transmission in the brains of animals, yet Hofmann stopped short of speculating about the possible brain mechanisms of his experience that he could have derived from that knowledge. 

LSD is the prototypic hallucinogen. Its molecular structure, shown in Figure 14.30, is very similar to that of serotonin, and this similarity permits LSD to... 

Little research has been conducted on how LSD interacts with other drugs. The most complete research is with antidepressant drugs because these commonly prescribed medications affect the same brain chemical, serotonin, that LSD does. There are three types of antidepressants, and each interacts differently with LSD ... 

Backstrom JR, Chang MS, Chu H, Niswender CM, Sanders-Bush E. Agonist-directed signaling of serotonin 5-HT2C receptors differences between serotonin and lysergic acid diethylamide (LSD). Neuropsychopharmacology 1999 21 77S-81S. 

It is still possible that serotonin and dopamine have something to do with LSD s effects, but after almost four decades of investigation of this compound, there s still no clear and accepted explanation for LSD s action. Speculating on the mystery surrounding the psychoactive agent he discovered, Albert Hofmann wrote ... 

Chronic administration of a monoamine oxidase inhibitor causes a subjective reduction in the effects of LSD, perhaps due to differential changes in central serotonin and dopamine receptor systems (66). 

It is interesting to contemplate the structural similarity predicted for LSD and serotonin and the known CNS activity of the former and to compare this with the CNS activity and structure of the cannibinol metabolite, ll-hydroxy-A9-tetrahydrocannabinol. It is conceivable that similar mechanisms may prevail in the CNS as a result of similar stereochemical presentations of comparable charged atoms to the serotonin receptor. 

Siegal and Salinas state that fluorescence studies reveal strong interaction between serotonin and nucleic acids. Yielding and Sterglanz report an interaction between LSD and native DNA, but not denatured DNA or RNA, using a reduction of native flu-... 

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