Psychedelics, Glutamate, and Neuroimaging Studies

A commentary critiques a prior article on psychedelic research, arguing it underrepresents the role of glutamate in psychedelic neurochemistry and incorrectly claims that psilocybin is the only classic psychedelic studied with human neuroimaging. The commentary notes that head-twitch behavior, a mouse proxy for human psychedelic action, depends on metabotropic glutamate 2 receptors co-expressed with 5-HT2A receptors. It also lists human neuroimaging studies of mescaline, dimethyltryptamine, and ayahuasca. The commentary raises unresolved questions about discrepancies between intravenous psilocybin studies showing decreased cerebral blood flow and oral psilocybin studies showing increased glucose metabolism.

Study at a glance

Abstract

The article by Icaza and Mashour1 is a very interesting article because it presents a topic of investigation that is currently attracting the attention of pharmacologists, neuroscientists, and biological psychiatrists around the globe: human research with psychedelic compounds. The text brings important information regarding the history and pharmacology of psychedelics but presents important limitations that are discussed below.In the first place, by focusing the neurochemistry discussion on N-methyl-d-aspartate antagonism and γ-aminobutyric acidergic activity in interneurons, the text narrows its focus and presents limited information regarding the importance of glutamate in the neurochemistry of the effects produced by psychedelic drugs. The head-twitch behavioral response, a mouse behavioral proxy of human psychedelic action, is induced by all psychedelic 5-HT2A receptor agonists, and this behavior is decreased in knockout mice for the metabotropic glutamate 2 (mGlu2) receptor.2,3 Moreover, this receptor has been shown to be expressed in close molecular proximity with the 5-HT2A receptor in tissue culture and mouse frontal cortex.3,4Second, Icaza and Mashour1 affirm that “Only one psychedelic drug—psilocybin—was discussed because this is the only classic psychedelic drug that has been studied with neuroimaging in humans.” This statement is not in line with the literature on psychedelic drugs, which is rich in neuroimaging human studies not only after administration of psilocybin5 but also after administration of the classic psychedelics mescaline,6 dimethyltryptamine,7,8 and the dimethyltryptamine-rich botanical preparation ayahuasca.9–12Finally, the literature on neuroimaging studies and psilocybin is not fully discussed and integrated in the article by Icaza and Mashour. There are important and contrasting data among the studies published to date, and these studies have not been included or discussed. How the decreases in cerebral blood flow and blood oxygen level–dependent signal detected after the intravenous administration of psilocybin in a functional magnetic resonance imaging study13 can be interpreted in light of the global increases in the cerebral metabolic rate of glucose after oral psilocybin administration in earlier positron emission tomography studies?14,15 Is there any pharmacokinetic or pharmacodynamic difference between intravenous and oral psilocybin administration, which could modify the brain’s rate of psilocin uptake, changing the neuroimaging patterns observed? These are the types of fundamental questions for future research.The author declares no competing interests.