TIFR-led study identifies brain region targeted by psychedelic drugs

MUMBAI: The use of psychedelic drugs is widely known to shift perception and consciousness, and reduce anxiety. However, despite long-standing clinical trials to help treat complex psychiatric disorders, there has been a poor understanding of where and how these drugs work in the brain.
Now a 16-member team led by the Tata Institute of Fundamental Research (TIFR), which comprises members from America’s Cornell, Yale and Columbia universities, has identified the precise part of the brain and the specific types of nerve cells targeted by the psychedelic drug DOI (dimethoxy-4-iodoamphetamine) which decreases anxiety. That part is the ventral hippocampus, a region of the brain involved in learning, memory and navigation.
“Human beings have been using psychedelics long before we even knew the definition of diseases like anxiety and depression though we can be sure these existed back then too,” said Vidita Vaidya, senior professor and co-chairperson, department of biological sciences, TIFR. “The drugs have been known to be used in indigenous and religious ceremonies in the Inca civilisation for instance. When psychedelics entered modern medicine, LSD (lysergic acid diethylamide) was synthesised. It was obvious even then that LSD and other psychedelic drugs do have an impact on the human brain, also potentially acting as therapeutic agents for depression, anxiety, and PTSD (post-traumatic stress disorder).”
The rampant use and abuse of psychedelics like LSD and mescaline (made from cactus) in the 1960s, largely by the hippie culture, led to their being banned by the US Drug Enforcement Agency in 1970. Since then, they are classified as Schedule 1 drugs, which limits their availability to researchers.
“Since the last decade, there is burgeoning depression and anxiety across the world,” said Vaidya. “The currently available drugs are poor; 30% of patients do not even respond to antidepressants. There looms a real crisis of good-quality therapeutic interventions. Over the last decade, therefore, clinical trials with psychedelics such as LSD and psilocybin (magic mushroom) for anxiety, substance abuse and PTSD have restarted.” Vaidya said that though it was known through anecdotal, empirical and clinical evidence that these drugs reduced anxiety, there was no understanding of where and how in the brain they did this. “That was the inspiration for our study,” she said. The study was published in the peer-reviewed scientific journal ‘Neuron’ on Tuesday evening.
Using two animal species of both sexes—rats and mice—the research team mapped how brain activity in the ventral hippocampus changed under the influence of DOI via serotonin 2A receptors. “Our work has identified a cellular trigger for how psychedelic drugs relieve anxiety,” said Vaidya. “Given that the ventral hippocampus does not appear to drive hallucinogenic action, our work opens up the possibility of designing psychedelic-inspired drugs that target anxiety without evoking potent hallucinations.”
Vaidya used an analogy to explain the findings of the work. “If you think of India as the brain, then the drug is working in Mumbai which is the ventral region of the hippocampus,” she said. “And within this region, a specific group of cells, say Marine Lines, gets stimulated with DOI and that’s how anxiety goes down. Developing novel psychedelic-inspired drug compounds that are modified to work on specific aspects of mental health diseases opens up the possibility of designing a whole new generation of drugs.”
Given that human trials on the use of psychedelic drugs to treat anxiety and depression are underway in different parts of the globe, the TIFR-led team said the results of its work would prove useful. This is because, being mammals, the brain of rats and mice has many similar cellular structures as the human brain. The brains of volunteers for psilocybin, for instance, can now be imaged to see if the drug hits the same region of the brain as the study found it did with mice and rats.
Dr Biju Viswanath of the National Institute of Mental Health and Neuroscience said that in clinical settings for anxiety and depression, the biggest challenge was that the medications needed six to eight weeks to act, and that about 50 percent of patients needed many medication trials, leading to a high possibility of treatment resistance. “Hence, there is a need to discover rapidly acting agents,” he said. “Dr Vaidya’s study provides key insights into the mechanisms of rapidly acting serotonergic psychedelics. Interestingly, they have mechanistic findings in the hippocampus, which is a well-established brain region affected in major depression, enhancing the relevance of this study.” Viswanath was not involved with the study.
What next? “Further experiments are focused on understanding the different circuits in the brain that contribute to the various behavioural effects of psychedelic drugs, such as the part of the brain responsible for the anti-depressant effects of psychedelics,” said Vaidya.