"It is the lack of serotonin which is the cause of the disorder." (D. W. Woolley, 1954)This hypothesis has influenced LSD researchers everywhere and the topic is still being hashed out; even in 2008, there were 2 reviews on "LSD and 5-HT". The 5-HT antimetabolite hypothesis has been disproved to 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 that differ by multiple atoms. It is very unfortunate that the resemblance between 5-HT and LSD has 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." (A. Schoenberg)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 play in the mode of action on the psyche (J. Smythies). Studies into LSD analogs, especially human studies of the Shulgin type, are rare 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. The first column indicates the LSD-like activity in humans, as assessed with Abramson's Cold Spring Harbor questionnaire, and the second column indicates anti-5-HT activity in the rat uterus preparation as reported by Cerletti and coworkers.
|From 5-HT pain|
|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 (H. H. Gettner, 1965). For example, MLD-41 and UML-491 had far greater anti-5-HT ability (370 and 400) than LSD (100) and had activities in humans that are 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." (E. Rothlin, 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 of cat brain. If LSD intoxication were due to a lack of 5-HT, then a reversal of LSD cat behavior 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 mescaline or LSD (B. E. Schwarz, 1956).
Opposite the 5-HT-antimetabolite theory is the hypothesis that the effects of LSD are due to an increase of 5-HT levels. This hypothesis does not account for early findings by Gaddum and Cerletti that LSD hardly ever potentiates the effect of 5-HT, and is generally not well-supported. An excess 5-HT alone does not produce hallucinogenic behavior, since carcinoid tumor patients, who exhibit some of the highest known concentrations of 5-HT in nature, tend to complain more of diarrhea and abdominal cramps than psychotic thinking. In addition, it was found that the psychotomimetic effects of LSD were not prevented by the hyperserotonemia present in carcinoid patients (R. Schneckloth, 1957). Further, the effects of LSD are probably unrelated to an enhancement of 5-HT levels, since treatments that elevate 5-HT itself, such as monoamine oxidase inhibitors or selective serotonin uptake blockers, are not hallucinogenic and may in fact, attenuate the subjective effects of hallucinogens in humans (G. K. Aghajanian, 1999).
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, yet, hallucinogen drug potency is not predicted by these measures. Quantum chemical parameters of a drug, such as its ionization potential energy or HOMO energy, are the most robust predictor of hallucinogen drug potency.
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.
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.
Aghajanian G. K. and G. J. Marek 1999. Serotonin and hallucinogens. Neuropsychopharmacology, 21, 16S-23S.
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.