The 5-HT edema reaction in rat paw was completely blocked by LSD and some LSD derivatives, lending support to the hypothesis that LSD functions as an anti-serotonin agent. Certain LSD derivatives actually antagonized the 5-HT swelling reaction more effectively than LSD. Preparations of UML-491, 1-methyl-lysergic acid butanolamide, had a similar effect as LSD in 4-6X smaller doses. Figure 2 below shows that pre-treatment with 1-methyl-lysergic acid butanolamide caused a dose-dependent decrease of 5-HT pain in the rat paw. Pain was assessed by taking measurements of the thickness of the paw every 15 minutes during two hours after the 5-HT injection. Time is plotted on the x-axis, and it can be seen that the maximal swelling occurred within the first half hour and then diminished. At a dose of 70 ug/kg, UML-491 almost completely prevented the swelling reaction.
Methylation of LSD occurs in the drugs MLD-41 and UML-491. These two drugs together with LSD were the most effective compounds at blocking 5-HT pain in the rat paw. Other LSD derivatives had no effect on the pain reaction, for example, hydrogenation of LSD led to a loss of blocking activity of nearly 90%.
Figure 4 below shows that UML-491 was more effective at inhibiting rat paw edema than LSD. The 2-position methyl group seems to be important for the physiological activity in this case, since UML-491 was more potent at inhibiting rat paw edema than lysergic acid butanolamide (unmethylated UML-491).
Interestingly, phenothiazine derivatives can also prevent 5-HT pain. Benditt and Rowley found that 5-HT- or histamine-edema of rat's paw could be prevented by the prior administration of chlorpromazine. Antihistamine drugs including phenothiazine, chlorpromazine, promethazine, and diethazine partly prevented 5-HT-edema, although these drugs were not as effective as LSD or UML-491. Relative to LSD (if LSD inhibits 5-HT edema by 100%), chlorpromazine inhibited 5-HT edema by 64%. UML-491 was the most potent derivative tested, inhibiting 5-HT edema by 440%, and MLD-41 inhibited 5-HT edema by 91%.
Drugs that block 5-HT or histamine are used to control allergic reactions. In guinea pigs who inhaled an aerosol spray of 5-HT or histamine, pre-treatment with LSD prevented death by anaphylactic shock. The research showing that LSD and UML-491 can prevent 5-HT-induced swelling is where Abramson found support for his idea that LSD and UML-491 could be used as therapeutic drugs in the treatment of allergies.
BENDITT E. P. and D. A. ROWLEY (1956). Antagonism of 5-hydroxytryptamine by chlorpromazine. Science 123, 24.
CERLETTI A. and W. DOEPFNER (1958). Comparative study on the serotonin antagonism of amide derivatives of lysergic acid and of ergot alkaloids. The Journal of Pharmacology and Experimental Therapy 122, 124-136.
DOEPFNER W. and A. CERLETTI (1958). Comparison of lysergic acid derivatives and antihistamines as inhibitors of the edema provoked in the rat's paw by serotonin. International Archives of Allergy and Applied Immunology 12, 89-97.