The search for psychedelic-like drugs opens the mind to scientists

A renewed interest in using psychedelic drugs to help treat psychiatric disorders is fueling a search for compounds that have similar effects but don't produce hallucinations.

The big picture: There is a tremendous need for new tools to help people with the mental and substance use disorders that are a leading cause of disability globally.

• Studies have discovered that using psilocybin — a compound found in psychedelic mushrooms — in tandem with psychotherapy can help some people with treatment-resistant depression, anxiety around life-threatening illness, addiction and other disorders.
• But the current treatments induce hallucinations and must be taken under medical supervision, and they may not be an option for people who have heart disease or a family history of schizophrenia.

How it works: When someone takes magic mushrooms or another classic psychedelic like LSD, the compounds in the drugs bind receptors for serotonin — a neurotransmitter that helps regulate mood — on the surface of brain cells.

• This can temporarily change communication between neurons in the brain, breaking down barriers between visual and information-assessing regions rich in a serotonin receptor called 5-HT2A, which leads to hallucinations, Inverse's Katie MacBride explains.

For some people with treatment-resistant depression, treatment with psilocybin found in psychedelic mushrooms can reduce symptoms of depression for up to six months.

• Psychedelics also appear to create new, long-lasting connections between brain cells — a rewiring known as neuroplasticity that some experts suspect is key to the drugs' benefits.
• But that's not entirely clear, says Matthew Johnson, who studies psychedelic drugs at Johns Hopkins University. "We don't know what is mediating the biological effects of the sustained change."

The big debate: Whether patients need to go on a mind-altering trip to reap the benefits of a psychedelic treatment.

• On the one hand: In several studies, people in experimental studies using psilocybin to address disorders like depression and anxiety attributed positive changes in their mood, attitude and behavior to the mystical experiences of a trip. That's led some researchers to argue that altered states are key to the therapy's benefits.
• And on the other: Hallucinations may contribute to the therapy's benefit but may not be necessary, says David Olson, a biochemist at the University of California Davis. He points to patients treated with psychedelics who don't have strong mystical experiences but still find treatment helpful and to MDMA, another psychedelic that usually doesn't produce hallucinations but has been shown to help treat PTSD.

Why it matters: For some people, hallucinations or mystical experiences may be a negative side effect of any potential drug.

• And rolling out a treatment that typically requires dozens of hours of therapy with more than one therapist to ensure safeguards for someone being put in a vulnerable state presents practical challenges, says Boris Heifets, a neuroscientist who studies psychedelic drugs at Stanford University.
• "For scaling and democratizing this treatment, non-hallucinogenic variants are really critical," says Olson, who is also a co-founder of Delix Therapeutics, which is trying to develop such drugs.
• Both psychedelic and psychedelic-like drugs are needed, says Johnson, adding non-hallucinogenic drugs might be taken every day (compared to a single dose of psilocybin) or to complement a psychedelic session. "We’ve been stuck in terms of psychiatric tools."

What's new: Olson and Lin Tian, who builds tools for studying neural circuits in her lab at UC Davis, developed a fluorescent sensor to screen whether a compound will have a hallucinogenic effect by detecting if and how it activates the serotonin receptor, 5-HT2A.

• The sensor could speed the testing of drug candidates — in the study Olson and Lin identified a non-hallucinogenic compound, AAZ-A-154, that is being tested further.
• In the future, Lin says, they want to use the sensor to pinpoint where a drug goes in the brain, how it acts on a receptor and how that affects behavior. "It's not just to find new drug candidates but also to understand the disease mechanism."
• Last year, a team of researchers used cryo-electron microscopy to determine the molecular structure of the serotonin 2A receptor when it is actively bound to psychedelic compounds, which could help identify compounds with a strong therapeutic effect but without accompanying hallucinations.

What to watch: A handful of companies are trying to identify and catalog non-hallucinogenic compounds.

• MagicMed, an early-stage startup based in Calgary, Canada, is using synthetic biology to create a library of compounds derived from psilocybin and DMT, says CEO Joseph Tucker.
• They're testing those molecules against different receptors — for serotonin but also other neurotransmitters — to try to identify potential drug candidates while teasing apart the basic science of which receptors are important for a drug's benefits and the brain circuits involved.

Go deeper: Psychedelic drug developers hit Wall Street (Axios)