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

Abstract

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 indolealkylamines, 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 Ki of 0.9 nM. The phenylisopropylamine DOI also displayed high affinity (Ki of 6 nM). Stereospecific interactions were found with DOB; (-) DOB had a Ki of 17 nM while (+) DOB had a Ki 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 Ki of greater than 10 microM. 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.

Receptor interaction profiles of novel psychoactive tryptamines compared with classic hallucinogens

“…The tryptamine with the lowest 5-HT 2A receptor affinity, DiPT, is psychoactive at 20-100 mg (Shulgin and Carter, 1980;Tittarelli et al, 2015). For the seven tryptamines that were evaluated in the present study, we found a significant correlation between 5-HT 2A receptor binding affinity and the estimated average doses at which the tryptamines are psychoactive in humans (Tittarelli et al, 2015) as previously shown for other hallucinogens (Sadzot et al, 1989;Titeler et al, 1988). In contrast, 5-HT 2A receptor activation potency did not correlate with the human doses.…”

“…The affinity of hallucinogens at the 5-HT 2A receptor but not at the 5-HT 1A receptor has been shown to correlate with psychoactive potency in humans (Sadzot et al, 1989;Titeler et al, 1988). The tryptamines that were tested in the present study all exhibited significantly lower affinity to the 5-HT 2A receptor compared with LSD.…”

Blockade of 5-HT2 Receptor Selectively Prevents MDMA-Induced Verbal Memory Impairment

“…The 5-HT 2A receptor agonists such as mCPP have been shown to decrease learning and memory in rats (Meneses, 1999). The same mechanism might be responsible for the decrement in learning and delayed recall following MDMA administration, as it has been previously demonstrated that MDMA possesses a moderate affinity for activating the 5-HT 2A receptor (Sadzot et al, 1989).…”

Chronic Lithium Administration to Rats Selectively Modifies 5-HT2A/2C Receptor-Mediated Brain Signaling Via Arachidonic Acid

“…The elevations also may be related to the ability of toxic doses of lithium to cause auditory or visual hallucinations (Hambrecht and Kaumeier, 1993) or photophobia (Pridmore et al, 1996). On the other hand, lithium's blocking of the k* increments in response to DOI, a recognized hallucinogen (Sadzot et al, 1989), in visual and auditory areas and the substantia nigra and locus coeruleus, may relate to its ability to reduce hallucinations in bipolar disorder (Goodnick and Meltzer, 1984;Potash et al, 2001;Rosenthal et al, 1979).…”

“…DOI, a hallucinogen (Sadzot et al, 1989), has a high and equal affinity for 5-HT 2A and 5-HT 2C receptors (http://kidb.cwru.edu/pdsp/php, 2003), which can be coupled to PLA 2 (Bayon et al, 1997;Qu et al, 2003). We chose a DOI dose of 1 mg/kg i.p.…”