The Neuroscience of Psychedelics


Whereas other investigators have focused primarily on clinical aspects of psychedelic drug action, and potential brain circuitry mechanisms underlying therapeutic efficacy to treat psychiatric disease using image-based techniques, Dr. Nichols has focused his research over the past 20 years on elucidating the cellular, molecular, and genetic effects of psychedelics in the brain, and is considered the leading international expert in this area.


What do psychedelics do at the receptor level? There are three main classes of psychedelics: Ergolines (like LSD), tryptamines (like psilocybin), and phenylisopropylamines (like mescaline). We, and others, have found that whereas all psychedelics activate the 5-HT2A receptor to produce behavioral changes, how drugs from each class, and drugs within a given class, activate the receptor can be different. The concept of how a given drug can differentially activate the same receptor compared to a different drug is called "Functional Selectivity." One of the areas of focus in the Nichol lab research is understanding how psychedelics activate the 5-HT2A receptor differently from serotonin, and how different psychedlics active the receptor from one another. These studies involve classic GPCR pharmacological studies examining effector pathway recruitment to understand structure-activity relationships between the ability of psychedelics to activate the receptor, alter beahviors, and produce an anti-inflammatory effect. We have made several discoveries, and have developed new ligands for the receptor biased towards specific bioogical outcomes with the goal of understanding how a particular ligand can activate the receptor to achieve a specific outcome to develop new ligands to for clinical use to treat psychiatric and inflammatory disorders.

Chronic Gene Expression

What do psychedelics do to gene expression in the brain? The answer to this depends on frequency of administration. Dr. Nichols was the first investigator to perform unbiased genetic screens for the effecs of LSD in the brain on gene expression. These pioneering studies revealed that after a single acute dose in rats, genes primarily regulating/enhancing the process of synaptic plasticity are induced in key areas of the brain. Since then, several researchers, including Dr. Nichols, have found that single administrations of LSD or other psychedelics have a rapid effect to increase synaptic density and complexity in the brain of both rodents and invertebrates. To study the effects of chronic LSD administration, Dr. Nichols collaborated with his father, Dr. David E. Nichols. They found that chronic treatment over three months results in abnormal behaviors that persist for weeks to months after discontinuation of drug. RNA-Seq gene expression experiemnts revealed that the expression of genes implicated in schizophrenia and bipolar disorder are significantly enriched in the brains of these rats, and they have proposed this as a new model for the study of psychosis.


Cortical 5-HT2A
How do psychedelics alter cellular function within the brain? Interestingly, administration of a psychedelic like LSD or DOI leads to significant transciptional activation of immediate early genes within brain cells, but these activated cells were shown to not express high levels of the target 5-HT2A receptor. Why would psychedelics lead to activation of cells not expressing receptor? To answer this question, we developed new methodology called Neurocytometry to isolate purified populations of different types of cells within the brain, and examined their molecular and genetic signatures. We found that psychedelics directly activate only 3-5% of neurons. Further examination revealed that the activated neurons express 4-5x more mRNA for the 5-HT2A receptor compared to neurons not directly activated by psychedelics, and are therefore more sensitive to their presence. We have called this sub-population of cortical neurons the "Trigger Population, " and hypothesize that their activation is necessary to initiate the overall effects in the CNS. In neurons that are not directly activated, however, receptor protein is internalized and localzed to the cell body.




Further, psychedelics lead to the direct activation of about 10% of GABA interneurons and about 10% of astrocytes. Interestingly, the nature of ensembles of activated cell types differ between brain regions, and how an individual cell type responds at the transciptional level differs between brain regions. Therefore, psychedelics produce a rapid and complex response of cell types activated, and types of responses depend on specific brain regions. These molecular and genetic differences likely alter cellular physiology that together underlie differential effects on brain network connectivity between regions observed in imaging studies. All together, the acute effects of psychedelics likely involve molecular and genetic changes to brain cells that result in differential activity and interconectedness, enhanced synaptic plasticity, and alterations in brain network connectivity to produce changes in sensory and cognitive processes (i.e. the psychedelic trip). It remains to be deterined, however, the mechanisms underlying therapeutic benefit to treat depression and substance use disorder. Ongoing studies in the Nichols lab are attempting to address these issues with new rodent models where they have shown that a single administration of psilocybin or LSD produce long-lasting and persistent antidepressant-like effects.