Just one dose of an LSD-like psychedelic drug alters the activation of genes in the brains of mice, resulting in long-lasting improvements in depression, anxiety, and other psychological disorders. According to a new study in the journal Cell Reports, the substance enhances genes that stimulate the formation of new brain connections, with these genetic alterations persisting for at least a week after the acute effects of the drug have worn off.
A number of recent studies have highlighted the mental health benefits of psychedelics, with substances such as psilocybin showing huge potential as a treatment for depression. Research has suggested that these therapeutic effects may last for weeks or even months following administration, yet the mechanisms underlying this long-term activity is not fully understood.
To investigate, the authors of this latest study trained mice to associate certain visual and olfactory cues with an electric shock. This resulted in a conditioned fear response, whereby the animals froze each time they encountered that cue, regardless of whether a shock was applied.
The researchers then treated the rodents with a psychedelic drug called 2,5-dimethoxy-4-iodoamphetamine (DOI), which is similar in structure to LSD. One day after the effects of the drug had worn off, mice showed a notable decrease in their conditioned fear response, and were less likely to freeze when encountering the cue they had previously learned to associate with pain.
In addition, the animals displayed reductions in depression and anxiety when assessed using behavioral tests 24 hours after receiving DOI. At this point, molecular analyses revealed that the neurons in the rodents’ prefrontal cortices had developed more dendritic spines, indicating that the drug rapidly stimulates the creation of new neuronal connections, resulting in reductions in psychological pathologies.
After seven days, the authors discovered alterations in chromatin organization within the cortical neurons of DOI-treated mice, leading to epigenetic changes at certain key genetic loci. In particular, the mice displayed an increase in the activation of genes associated with synaptic assembly, which would appear to explain the increase in neuronal connections.
“A large fraction of epigenetic changes in enhancer regions persist for at least 7 days after DOI administration and potentially constitute the molecular basis for the long-lasting effects,” write the authors. In other words, one dose of the drug appears to trigger changes in neuronal gene activation that last for a whole week.
Importantly, the researchers noted that DOI failed to produce any of these effects when administered to mice that had been bred to lack a serotonin receptor known as 5-HT2A. This receptor is believed to regulate the consciousness-altering effects of all classic psychedelics, and such a finding implies that the same receptor also underlies the therapeutic properties of these drugs.
Finally, the researchers report that many of the genes that are impacted by DOI also play a role in mental health disorders such as depression and schizophrenia. Though the study was carried out in mice, so not necessarily analogous to humans, they conclude that “epigenomic-driven changes in synaptic plasticity sustain psychedelics’ long-lasting antidepressant action but also warn about potential substrate overlap with genetic risks for certain psychiatric conditions.”