Hallucinogenic drug interactions at human brain 5-HT₂ receptors: implications for treating LSD-induced hallucinogenesis

It has been shown that the hallucinogenic potencies of LSD, the phenylisopropylamines, such as DOB (4-bromo-2,5-dimethoxyphenylisopropylamine) and DOI (4-iodo-2,5-dimethoxyphenylisopropylamine), and the indoleaklylamines, such as DMT (dimethyltryptamine) and 5-OMe-DMT (5-methoxy-dimethyltryptamine), strongly correlate with their in vitro 5-HT₂ receptor binding affinities in rat cortical homogenates. In order to ascertain if this correlation applies to human 5-HT₂ receptors as well, we examined the affinities of 13 psychoactive compounds at ³H-ketanserin-labelled 5-HT₂ receptors in human cortical samples. Both radioligand binding and autoradiographical procedures were used. As in rat brain d-LSD was the most potent displacer of ³H-ketanserin specific binding with a K_i of 0.9 nM. The phenylisopropylamine DOI also displayed high affinity (K_i of 6 nM). Stereospecific interactions were found with DOB; (-_ DOB had a K_i of 17 nM while (+) DOB had a K_i of 55 nM. The behaviorally active compound DOM (4-methyl-2,5-phenylisopropylamine) had an affinity of 162 nM while its behaviorally less active congener iso-DOM had an affinity of 6299 nM. The indolealkylamines 5-OMe-DMT and DMT competed with moderate affinities (207 and 462 nM, respectively). In general, Hill coefficients were significantly less than unity which is consistent with an agonist interaction with 5-HT₂ receptors. MDMA, a substituted amphetamine analog was inactive with a K_i of greater than 10 μM. A strong correlation was found for the hallucinogen affinities and human hallucinogenic potencies (r=0.97). Also, human and rat brain 5-HT₂ receptor affinities were strongly correlated (r=0.99). These results strongly support the hypothesis that the hallucinogenic effects of these drugs in humans are mediated in whole or in part via 5-HT₂ receptors. Furthermore, these studies imply that treatment with 5-HT₂ receptor antagonists may be effective in reversing the hallucinogenic effects caused by the ingestion, of LSD and LSD-like drugs.