Mind-Bender, Mind-Fixer? Researchers Investigate Targeted Psychoactive Therapies Without the Trip

“I was in the room,” says Natasha Mason, an assistant professor at Maastricht University. Mason and colleagues at Maastricht study the effects of a psychedelic naturally found in toad venom on individuals with treatment-resistant depression. “Some seemed like a whole new person. And most were still in remission a week later” — the duration of the initial, proof-of-concept study.

Some research on psychedelics and depression includes toad venom, or 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT). This psychedelic substance is in various plant species and the glands of the Colorado River toad (Incilius alvarius), pictured above.

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The persistence of therapeutic benefits long after these drugs have been cleared from the body appears to be tied to their ability to enhance neuroplasticity, promoting the growth of neuronal connections. Using a technique for live brain imaging in mice, Alex Kwan, associate professor at the Meinig School of Biomedical Engineering at Cornell University, discovered a single dose of psilocybin boosts the density of synapses in the frontal cortex. “When we go back a month later,” he says, “some of those new connections are still there.” And studies demonstrate, in the case of ketamine, selectively eliminating these drug-induced connections quashes the antidepressant activity. 

Understanding the mechanisms by which drugs like ketamine and psilocybin — and even the antidepressants currently on the market — regulate neuroplasticity and mood could uncover common molecular targets or pathways that could lead to the development of more effective, longer lasting treatments. “Perhaps ketamine could be used to initiate the cascade, but another drug that targets a downstream component of the pathway could sustain the effects,” says Lisa Monteggia, professor of pharmacology and Barlow Family director of the Vanderbilt Brain Institute at Vanderbilt University in Nashville.

Psilocybin, the hallucinogenic active ingredient in “magic mushrooms” pictured above, and other psychedelics like ketamine have gained traction for study as some scientists found they can assist patients during certain therapies in clinical settings.

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Such reinforcement doesn’t even have to be pharmaceutical. It could come from something like transcranial magnetic stimulation, or even cognitive behavioral training, or talk therapy applied during the period in which neural plasticity continues to be elevated. “We could capitalize on that window of opportunity to enhance the therapeutic potential of these substances,” says Mason. 

Passage Without the Trip

But not everyone is keen on a hallucinogenic odyssey — much less an ongoing series of them. “It can be an amazing experience,” says translational neurobiologist and clinical neurologist, Gitte Moos Knudsen, at the University of Copenhagen, who notes it’s often quite exhausting. “It’s not something you want to repeat too often.” 

Knudsen’s work finds psychedelics disrupt the normal communication circuits within the cerebral cortex, an action that may contribute to the feeling of detaching from oneself and transcending time and space.

Can these drugs provide clinical benefits without the mind-altering experience?

For those considering a psychoactive therapy, the question then becomes: Can these drugs provide clinical benefits without the mind-altering experience? It’s possible a change in perspective actually facilitates the therapeutic process, allowing individuals to abandon obsessive rumination and establish healthier patterns of thinking and behaving.

At the same time, a growing number of studies suggest the trip may not always be required. In research presented at Neuroscience 2022, Katherine Nautiyal, assistant professor of psychology and brain sciences at Dartmouth College, finds psilocybin’s ability to relieve certain depressive behaviors in mice may depend on its ability to interact with a subtype of serotonin receptor not known to be involved in the chemical’s hallucinogenic effects. Although Nautiyal is ultimately agnostic about the potential for decoupling psychedelics’ clinical and consciousness-altering effects, she stresses that “understanding the changes that are occurring in the brain to support their long-term therapeutic benefits could open up new avenues for understanding how to treat depression.” 

Others are using the powers of chemistry to design molecules that interact with the serotonin receptor associated with psychedelic effects, but by inducing plasticity without triggering hallucinations. Using a computational approach, Bryan Roth, the Michael Hooker Distinguished Professor of Pharmacology at the University of North Carolina, Chapel Hill, has screened trillions of novel molecules for their ability to interact with the psychedelic serotonin receptor. Of those, Roth says, two show antidepressant-like activity, but no psychedelic action in mice. “Of course, we also discovered tons of new psychedelics,” he adds. “But we don’t feel like the world needs more of those right now.”

"Over the last few years, several labs reported about a dozen new compounds that supposedly activate these receptors without indicating a trip."

These non-psychedelic psychedelics may engage different downstream signaling pathways than their classical counterparts, says Roth. But how they work remains to be seen. “Over the last few years, several labs reported about a dozen new compounds that supposedly activate these receptors without indicating a trip,” Kwan says, noting they have been studied in cell lines and animals, and it will take two or three years for them to be tested in the clinic. “We just have to wait and see whether they cause a trip and whether they have benefits in treating depression.”

If they function as anticipated, Roth says these substances have the potential to revolutionize neuropsychiatric treatment. “We don’t have any treatments where you take one dose and then you're fine for six months,” he notes. “So this could transform how we treat mental disorders.”