The Depressed Brain may Rewire with Psychedelics

Some psychedelic drugs, such as psilocybin and MDMA, how promise in treating depression and post-traumatic stress disorder. They do this by encouraging the growth of new connections between neurons in the brain. This ability of the brain to make new connections is called plasticity. However, exactly how these drugs promote plasticity has been unclear.

It’s important to develop related drugs that can promote brain plasticity without causing ‘a trip’. 

Dr. David Olson and his research team from the University of California, Davis, have developed a sensor that can tell which drugs that attach to a receptor called 5-HT2AR in neurons have hallucinogenic properties and which do not. This study aims to figure out why only some of the drugs that bind to 5-HT2AR are capable of promoting brain plasticity. Brain plasticity refers to the brain’s ability to form new connections. Improved plasticity can help treat mental health disorders like depression and post-traumatic stress disorder.

Researchers discovered that a compound’s ability to enter a neuron and bind to receptors inside the cell determines how well it can promote the growth of dendritic spines. Dendritic spines are structures that help to connect neurons in the brain. The research team also found that clusters of the 5-HT2AR receptor could be found both inside and outside the neurons. The compounds that could bind to the receptors inside the neurons caused the dendritic spines to grow. But, the compounds that only bind to the receptors on the outer surface of neurons, such as serotonin, did not have the same effect.

When they used an electrical current to allow compounds like serotonin to enter neurons, the compounds promoted dendritic spine growth. Similar results were seen in neurons engineered to make a protein that can pull serotonin into cells. Neurons that took serotonin inside formed new dendritic spines. Neurons where serotonin could only bind to exterior 5-HT2ARs did not. When they tested this phenomenon in living brains of mice engineered to make a protein that can bring serotonin into neurons, the mice formed substantially more dendritic spines than in mice without the protein. The mice also showed improvements in a behavior test thought to be relevant to depression.

These results suggest that the 5-HT2ARs inside and outside of neurons activate different cell-signaling pathways. The researchers hope that these results will help develop better drugs that can safely activate the pathways for brain plasticity while avoiding hallucinogenic effects.

Interventional psychiatric treatments like Ketamine and Spravato® are already in use for depression including at Heading Health centers in Austin and Dallas. The addition of more psychedelic treatments, and understanding of each one’s particular best use is continuing to be researched with promising results offering hope that psychiatric researchers are moving closer to understanding how psychedelics can be safely administered for the rapid treatment of long-standing stress disorders. 

The research is now focusing on decoding the biological mechanisms behind how psychedelics can affect the brain and how the effects of these psychoactive drugs can be harnessed for therapeutic benefits. 

The research team is exploring the effects of psychedelics on the body’s serotonin, glutamate and dopamine systems, as well as their impact on the hypothalamic-pituitary-adrenal axis, which plays a key role in the body’s stress response. They hope that by understanding the underlying biology of these substances, they can develop more effective treatments to help people suffering from mental illness. In addition, they are also studying the potential of psychedelics to enhance cognitive performance, creativity and even spirituality. Ultimately, the researchers hope that by better understanding the biochemistry of psychedelics, they can develop more effective treatments to help people suffering from mental illness and even improve overall well-being.