Psychedelic Drug DOI Pinpoints Anxiety Circuits Avoiding Hallucinogenic Effects, Study Finds

In a groundbreaking study published in Neuron, researchers at Johns Hopkins University uncovered how the psychedelic drug DOI (2,5-dimethoxy-4-iodoamphetamine) reduces anxiety by activating particular neurons in the brain. The research looks at a specific type of brain cell called parvalbumin-positive interneurons, wich are found in the ventral hippocampus and help control how other brain cells communicate with each other.

As PsyPost reported, results revealed that DOI, which has calming effects, works by influencing these particular cells. This discovery marks a step forward in understanding psychedelics’ potential for treating anxiety, revealing critical distinctions in brain activity associated with therapeutic benefits versus hallucinogenic effects.

Activating Anxiety-Reducing Neurons

The research team, led by Praachi Tiwari, conducted behavioral tests on mice and rats to determine DOI’s impact on anxiety. Rodents given DOI spent more time in open, anxiety-inducing spaces, such as the elevated plus maze's open arms or the center of an open field. These behaviors are recognized indicators of reduced anxiety in animal models. "The serotonergic system is known to be implicated in the regulation of mood-related disorders. The fact that psychedelics modulate this neurotransmitter system is really intriguing," Tiwari explained, highlighting the serotonin system’s role in mood and anxiety regulation.

Targeting The Ventral Hippocampus

To understand which brain regions DOI activates, researchers administered the drug directly into the ventral hippocampus, a region involved in processing emotions and linked to anxiety. This approach confirmed that the ventral hippocampus was a central area of action. They also noticed that DOI specifically gets these parvalbumin-positive interneurons working more actively. These interneurons usually help keep other brain cells in check. By doing this, they seem to calm down the parts of the brain that are involved in anxiety, essentially reducing the overall activity in those areas and helping to relieve anxiety.

Distinguishing Therapeutic And Hallucinogenic Effects

A crucial aspect of the study is its revelation that DOI's anxiety-reducing properties do not coincide with its hallucinogenic effects. Unlike typical psychedelic responses, DOI's activation of the ventral hippocampus did not trigger the head-twitch response in rodents, a behavior often linked to hallucinations. "This neural circuit does not seemingly overlap with the circuits that potentially drive the hallucinogenic-like response in rodents," Tiwari noted. This distinction raises the possibility of developing targeted anxiety treatments based on psychedelics without the hallucinogenic side effects.

Implications And Future Directions

While the study's findings are promising, they are limited to animal models. Anxiety in humans is more complex, involving multiple brain regions. Future research is necessary to confirm whether these findings apply to humans. Additionally, the study only examined DOI's short-term effects, leaving questions about long-term impacts on chronic anxiety. "We cannot preclude the possibility that there may be other regions in the brain that act independently or in tandem with the ventral hippocampus to evoke a decline in anxiety-like response upon acute DOI action," Tiwari explained.

As research continues, the DOI and DOC are in the midst of a legal back-and-forth, awaiting hearings scheduled by the DEA in November to deliberate on their possible banning.

Cover image made with AI