After more than 60 years in the woodshed, psychedelics are enjoying a medical renaissance in clinical trials and scientific research as potential treatments for a range of mental health conditions from anxiety to Alzheimer’s disease.
In the 1950s and 1960s, psychedelics or hallucinogens, such as psilocybin and LSD, were studied for treatment of mood disorders as part of psychotherapy, but the research was cut short for political, not medical reasons.
The resurgence of interest in the therapeutic value of psychedelics includes LSD and psilocybin, peyote and dimethyltryptamines (DMT), many of which are under study in hundreds of clinical trials for mental illnesses. A major difference from past attention to psychedelics is the tools available to researchers in understanding how these compounds affect the brain and behavior at the neuronal level.
Stem cell neurobiologist Stevens Rehen, Ph.D., Scientist of the D’Or Institute for Research and Education and Professor of Biological Sciences at the Federal University of Rio de Janeiro, has been studying substances in ayahuasca, a plant-based tea used in spiritual ceremonies in South America as well and other psychedelics. “Studies have shown that substances like psilocybin, found in magic mushrooms, and the brew ayahuasca can have a profound effect on depression and anxiety, often providing relief where other treatments have failed,” he said. “These substances are believed to work by disrupting default brain activity patterns and fostering new neuronal connections.”
It’s this latter activity, at the neuronal level, where Dr. Rehen is studying the impact of psychedelics. He accomplishes this significant research feat by creating mini-brains or brain organoids artificially grown in vitro from human pluripotent stem cells. By adding psychedelic compounds to the organoids, he can discover how the proteins inside cells are altered. “When you think about the most used kinds of antidepressants, they try to work by modulating brain chemistry, including the levels of neurotransmitters like serotonin, to alleviate depressive symptoms and improve mood. They often target the reuptake or breakdown of serotonin, aiming to increase its availability in the brain.,” Dr. Rehen said. “However, recent research from the University of California, Davis, suggests that the effectiveness of antidepressants may not solely be determined by the amount of serotonin, but rather by the specific receptors within neurons that are influenced by this neurotransmitter,” he added. “The study emphasizes the importance of receptor location in understanding the effects of psychedelic drugs. Based on this recent scientific article, psychedelics activate serotoninergic receptors inside cells, not only the cell membrane receptors targeted by serotonin.”
This insight, Dr. Rehen suggested, could lead to targeted delivery of psychedelic compounds within the neurons. “If you’re able to get one psychedelic inside the neurons,” he added, “theoretically, it could improve its effects and make it more efficient. That said, we may speculate that there are potential advantages of being able to better target where the psychedelic will work.”
Studies by AGS Therapeutics demonstrate the company’s delivery system, microalgae extracellular vesicles (MEVs), can deliver molecules by intranasal administration through the nose into neurons in the olfactory bulb. The MEV therapeutics then travel inside the neurons along the olfactory pathway into many regions of the brain. In theory, Dr. Rehen said, using MEVs to deliver psychedelics into neurons would have advantages over systemic administration. “Intranasal delivery of therapeutics could potentially allow for a direct pathway to the brain,” he added. “MEV-mediated delivery directly inside the neurons could allow for a better targeting of the intracellular receptors. But it’s important to note that more research is needed.”
In opening a window to how psychedelics work inside neurons, Dr. Rehen’s research is broadening an understanding of neuroplasticity, which is the brain’s ability to change, reorganize and grow neural networks resulting from internal and external stimuli. “We showed that more than 1,000 proteins in neurons may be altered when exposed to different psychedelics,” he said, “and based on this research we are able to identify signaling pathways that could explain the effects of the psychedelics.”
For example, Dr. Rehen observed, “Exposing brain organoids to various psychedelics leads to noticeable changes in protein levels. These fluctuations, whether resulting in decreased or increased levels of specific proteins, directly influence cellular behavior and have a significant impact on brain function.” In addition, he said, “What we and other groups are showing is that psychedelics not only affect neuroplasticity, but also inflammation that causes neurodegenerative diseases.”
Looking inside neurons to see how they respond to psychedelics, Dr. Rehen said, can make scientists better understand the effects that go beyond those already known, potentially enabling them to discover new kinds of medications for mental health conditions.