"It is the lack of serotonin which is the cause of the disorder." (Woolley,D.W. 1954)This hypothesis has influenced LSD researchers everywhere and the topic is still being hashed out; even in 2008, there were 2 reviews written on "LSD and 5-HT". The 5-HT antimetabolite hypothesis has been disproved for the most part, though it still gains in popularity by conforming with the contemporary preoccupation with serotonin amongst neurophysiologists and behavioral scientists.
Though there is some chemical resemblance between 5-HT and LSD, they are two very different molecules. The resemblance between 5-HT and LSD may have side-tracked researchers from focusing on something far more interesting -- that there are some single-atom alterations to the structure of LSD, such as bromine in the 2-position (BOL-148), that yield drugs that are completely ineffective compared to LSD!
"One atom of hydrogen more, one less of carbon, changes an uninteresting substance into a pigment or even an explosive." (Schoenberg,A.)The important field of structure-activity relationships in LSD and its derivatives has been strangely neglected while researchers have looked into correlations between LSD and 5-HT. The research program should have included the synthesis of a number of analogs of LSD according to systematic principles to determine the role of the details in its molecular structure that play in the mode of action on the psyche (J. Smythies). Yet studies of LSD analogs, especially human studies of the Shulgin type, are hard to find in the literature. They are far fewer in number than studies that have compared the actions of LSD with 5-HT.
One strike against the 5-HT-antimetabolite LSD hypothesis is the fact that a number of derivatives of LSD-25 are more potent antagonists of 5-HT peripherally but lack psychotomimetic activity. MLD-41 and UML-491 are classic examples of LSD derivatives with exceptional anti-5-HT activity, but that are inactive at LSD dose levels.
Table 1 below lists different LSD derivatives, along with the psychotimemetic activity, as assessed with Abramson's Cold Spring Harbor questionnaire, and anti-5-HT activity in the rat uterus preparation as reported by Cerletti and coworkers.
No clear correlation was found between the effective dose of a hallucinogenic drug and its potency in blocking the action of 5-HT on isolated smooth muscle preparations (Gettner et al., 1965). For example, MLD-41 (370) and UML-491 (400) had greater anti-5-HT ability than LSD (100) and had psychotomimetic activities in humans rated at 36 and 0.66 as compared to LSD at 100.
BOL-148 has about the same anti-5-HT ability as LSD, and its activity is 7.2 as compared to LSD at 100. Rothlin said,
". . . it is difficult to admit a correlation of the psychic effects induced by LSD and its anti-5-HT property, since 2-brom-LSD possesses the same anti-5-HT activity in vitro and in vivo, but it lacks the psychotogenic action." (Rothlin,E. 1957)
One of the barriers for studying 5-HT is the lack of absorption of 5-HT when it is delivered intravenously, since 5-HT doesn't cross the blood-brain barrier. This problem can be circumvented if 5-HT is delivered straight to the ventricles. If LSD worked by blocking 5-HT neurotransmission, then a reversal of LSD behavior in the cat would be expected when 5-HT is delivered intraventricularly to brain. This experiment was performed by Schwarz and colleagues, in 1956, who found no change in cat behavior when 5-HT was administered intraventricularly, at a time period after dosing with mescaline or LSD (Schwarz et al., 1956).
As a further strike against the 5-HT-antimetabolite theory of LSD intoxication, it was found that the psychotomimetic effects of LSD were not prevented by the hyperserotonemia present in carcinoid patients (Schneckloth et al., 1957). This research would seem to have the definitive word on whether LSD works by blocking serotonin.
The relationship between LSD and 5-HT is complex. LSD is one of the most specific serotonin inhibitors within a large group of several amide derivatives of lysergic acid, and MLD-41 and UML-491 together with LSD are amongst the most powerful anti-serotonin drugs studied in the model of 5-HT edema, but hallucinogen drug potency is not predicted by these measures. Lipophilicity and quantum chemical parameters of a drug, such as its ionization potential energy or HOMO energy, are the most robust predictor of hallucinogen drug potency.
Woolley D. W. and E. Shaw (1954). A biochemical and pharmacological suggestion about certain mental disorders. Proceedings of the National Academy of Sciences of the United States of America 40, 228-231.
SCHWARZ B. E., K. G. WAKIM, R. G. BICKFORD and F. R. LICHTENHELD (1956). Behavioral and electroencephalographic effects of hallucinogenic drugs; changes in cats on intraventricular injection. A.M.A. Archives of neurology and psychiatry 75, 83-90.
Rothlin E. (1957). Pharmacology of lysergic acid diethylamide and some of its related compounds. The Journal of pharmacy and pharmacology 9, 569-587.
SCHNECKLOTH R., I. H. PAGE, F. D. GRECO and A. C. CORCORAN (1957). Effects of serotonin antagonists in normal subjects and patients with carcinoid tumors. Circulation 16, 523-532.
Gettner H. H., A. Rolo and H. A. Abramson (1965). Lysergic acid diethylamide (LSD 25). 36. Comparison of effect of methysergide (UML 491) on goldfish and Siamese fighting fish. The Journal of psychology 61, 87-92.
Green A. R. (2008). Gaddum and LSD: the birth and growth of experimental and clinical neuropharmacology research on 5-HT in the UK. British journal of pharmacology 154, 1583-1599.