A mushroom of the genus Psilocybe, which contains the psychoactive chemical psilocybin, in a lab

Why scientists want to create psychedelics that give better trips

Drugs modeled on natural compounds could help people with anxiety, depression, and addiction. But can side effects, like long-and-winding trips, be eliminated while keeping the therapeutic benefits?

A mushroom of the genus Psilocybe, which contains the psychoactive compound psilocybin.
Photograph by Alana Paterson, The New York Times/Redux

When Matthew Johnson, a psychedelic drug researcher at John Hopkins Medicine, studies the effects of psilocybin on patients suffering from depression or addiction, he is careful to exclude anyone with heart disease. That’s because the drug—the active ingredient in magic mushrooms—has the potential to harm the heart. Other side effects have also emerged in the university’s clinical trials, including nausea.

Small studies like Johnson’s have confirmed the power of psychedelics to treat certain types of mental illness but have also raised concerns about side effects. That has spurred biotech and pharmaceutical companies, drawn to the tremendous potential, to try to design new psychedelic compounds without the downsides—including, perhaps, the long-and-winding trip for which they are famous. Most companies are still in the early stages of identifying molecules and testing them in laboratory animals.

“While big, definitive studies still need to be done, it’s looking increasingly clear that psychedelic medicines can be of enormous benefit to individuals with depression, addiction, and other common disorders,” says Christopher Pittenger, director of the Yale Program for Psychedelic Science.

Psychedelics include drugs like lysergic acid diethylamide (LSD), ayahuasca, mescaline, and other substances that alter consciousness, as well as entactogens, a related class that includes methylenedioxy-methamphetamine (MDMA). Overall, experts consider the compounds to be generally safe. With millions of Americans struggling with mental health concerns, according to the U.S. Centers for Disease Control and Prevention, there’s an urgent need for new therapies.

Research has shown that when clinical trial volunteers receive specific doses of these drugs under close supervision and with careful preparation, just one or two sessions may provide effective and lasting treatment for a wide range of mental-health disorders, including depression, anxiety, and addiction.

In one of Johnson’s studies, 24 people with severe depression took two doses of psilocybin accompanied by supportive psychotherapy. A year later, 58 percent were still in remission. (Other research has found remission rates from psychotherapy alone to be closer to one third.) The nonprofit Multidisciplinary Association for Psychedelic Studies (MAPS) has reported positive results for post-traumatic stress disorder with MDMA (aka ecstasy or Molly); two months after one treatment, 67 percent of participants no longer met the criteria for PTSD. MAPS expects to receive approval for this treatment from the U.S. Food and Drug Administration in the next few years. Still, the association cites potential side effects, ranging from dry mouth and teeth grinding to more concerning ones, such as fainting or spiking blood pressure.

Created for the plant, not you

Although a few psychedelic compounds, like LSD, were synthesized in a lab, most are derived from nature. This means the properties we associate with them evolved to protect the plant, such as by discouraging predators, not to treat humans, says Joseph Tucker, CEO of Enveric Biosciences, a two-year-old Cambridge, Massachusetts-based startup. In this way, psychedelics are no different from many other drugs.

“The history of the pharmaceutical industry is about being inspired by nature, and then making something in the lab to make it safer, increase its efficacy, have fewer side effects, and make it easier to manufacturer,” he says, pointing to the classic example: aspirin, which was modeled on a compound in willow tree bark.

Companies are also looking to improve the timing, intensity, and duration of the psychedelic experience. Psychedelics can take an hour or two to begin working, and once they do the experience lingers; about 10 hours for LSD trips and six for psilocybin. That’s too long to remain under the active care of a medical professional. And because the psychedelic experience can be intense, those with a history of psychosis or schizophrenia are generally excluded from clinical trials on psychedelic drugs.

“Wouldn’t it be better if you could take a psychedelic and have it start working in five or 10 minutes and if your session could last one or two hours—and without the GI upset? This is all possible,” Tucker says.

Of course, another key driver of innovation is the fact that companies can’t patent a natural organism like a magic mushroom or a cactus, which is the source of mescaline. But they can own the rights to an entirely new molecule or a new formulation or delivery system.

“There’s a real business opportunity now, when even a few years ago there wasn’t,” notes Evan Levine, cofounder and CEO of three-year-old startup PsyBio Therapeutics in Oxford, Ohio, referring to the growing acceptance by mainstream medical professionals of the potential for psychedelic therapy.

This profit motive isn’t a bad thing, Johns Hopkins’ Johnson says, since it incentivizes companies to conduct the extensive and expensive studies required to prove the drugs are safe and effective. “We do need credible investments by pharmaceutical companies and start-ups,” he says.

Leaning on computer power

To create molecules that improve on nature, some companies are turning to artificial intelligence. The London-based company April19 Discovery was launched by computer scientists two years ago specifically to design new psychedelic drugs.

To test one of their drug-design AI programs, computers were asked to potentially identify molecules with psychedelic properties from a large database of compounds. The molecules were then compared with the 230 compounds discovered in the mid-20th century by the renowned biochemist Alexander Shulgin, who personally ingested each compound as he screened them for psychedelic effects. April19 flagged nearly 200 of these compounds within a few days, says Suran Goonatilake, a cofounder and an artificial intelligence professor at University College London.

Most classic psychedelics are thought to work by activating a class of serotonin receptors in the brain, called 5-HT2A. But within the group of molecules that can stimulate these receptors, each causes unique biochemical reactions that could trigger or evade the unwanted side-effects. AI can predict some of these interactions, Goonatilake says. Better compounds might also avoid exciting the 5-HT2B receptors that many psychedelics activate—but which are associated with cardiotoxicity after multiple uses. So far, the company has found dozens of molecules it plans to test in living animals.

April19 also collaborated with Enveric to evaluate the 500 compounds it had previously identified in a “psybrary” of potentials. Using AI enabled Enveric to substantially narrow down its drug candidates to the most promising ones, Tucker says. Late next year the company is planning to take its most promising molecules for treating anxiety and addiction into clinical trials.

Tweaking molecules in the laboratory can be a humbling experience, says Jackie von Salm, cofounder of the Tampa, Florida-based startup Psilera, which is using machine learning to help it identify potentially beneficial compounds. “It’s shocking how if you change just one or two atoms, you dramatically change the [psychedelic’s] activity,” she says. “It really teaches you that if you're working with the brain, you really should start small,” she says.

Other innovations are also being explored to rapidly identify candidate psychedelics. University of California, Davis biochemists have engineered a genetically modified protein sensor they’ve named psychLight. Whenever a molecule binds to the serotonin 5-HT2A receptor on a microscope slide it changes shape, which causes the fluorescent protein to light up.

In research published last year in the journal Cell, the sensor successfully predicted the biological effects of a number of molecules—including one that did not create a psychedelic trip but that nonetheless produced a long-lasting, antidepressant-like change in animals. “We can go through a thousand compounds in a week,” says Lin Tian, who helped developed the technique and is vice chair of molecular medicine at the university. “This is not a prediction from a computer, but a real biological reaction that we observe.”

Of course, tinkering with psychedelic drug molecules is not without risks. “There’s always a chance that when you’re trying to reduce hallucinations you supercharge them instead, or maybe you end up increasing cardiotoxicity instead of removing it,” Psilera’s von Salm notes.

Eliminating the high?

To use psychedelics as treatments, some companies believe it might be helpful to reduce or eliminate the consciousness-altering trip to make the experience less disruptive to a person’s life. However, whether it’s possible to achieve mental-health benefits without the trip, which in many ways defines psychedelics and entactogens, is unknown.

Psilera is testing using smaller doses of the psychedelic dimethyltryptamine (DMT), a drug also called Dimitri. Because DMT is degraded when swallowed—most street drug users smoke or inject it—the company patented a skin patch it hopes will deliver a mid-range, steady dose that doesn’t cause hallucinations but still produces the lasting brain changes believed to be behind its therapeutic effects.

Psilera is also hunting for new compounds. Several tested in animals caused fewer hallucinations yet were found in behavioral studies and brain dissections to retain some of the antidepressant and antianxiety effects of psychedelics, von Salm says. (If you’re wondering how scientists know whether an animal is having a trip, they use what is known as the “wet-dog” shake. Seemingly trying to throw off the intensive, altered images, stoned animals repeatedly twitch their heads. When they don’t shake their heads it’s a sign, scientists believe, that the hallucinations have been reduced or eliminated.)

Another company, New York-based MindMed, has modeled its non-hallucinogenic proprietary compound, 18-MC, on the West African psychedelic ibogaine—derived from the roots of the iboga shrub. Rat studies suggest the drug is useful for treating substance abuse but doesn’t cause the heart rhythm issues associated with ibogaine, according to the company.

PsyBio Therapeutics’ compound, not yet named, has been found to improve PTSD in lab animals without generating a high, says Levine. He believes such a drug could be particularly beneficial for severely anxious patients because they may not feel comfortable surrendering control of their consciousness.

Published research does confirm that something therapeutic happens even when the high is stripped away. In one study by University of California, Davis, scientists, rodents were subjected to mild stressors, then given a dose of a non-hallucinogenic cousin of ibogaine called tabernantholog. Imaging studies showed the drug promoted the regrowth of parts of certain brain neurons that the stress had diminished, the researchers reported in Molecular Psychiatry.

Altering the part of the drug molecule that stimulates the consciousness-altering experience could prove useful because the way classic psychedelics are used is too inefficient and expensive for widescale deployment, Yale’s Pittenger says. “If the field can develop strategies to capture the antidepressant or anti-addiction effects in a pill without major effects on consciousness,” he says, “it will become much easier to imagine bringing new benefit to the millions who need it.”

But Hopkins’ Johnson doubts non-hallucinogenic substances will bring lasting changes to people who have intractable mental-health problems with just one or two psychedelic doses; instead, he thinks they would likely require continuous use. But such drugs, Johnson believes, may still prove more effective than antidepressants and other medicines currently available.

One way to avoid altering consciousness is by taking a microdose of a standard psychedelic, or a small percentage of an active amount, says Justin Hanka, founder and CEO of the Melbourne, Australia-based company MindBio Therapeutics. But while people are using this method to self-medicate, it has not been rigorously studied in humans. (Here’s what the experts say about microdosing.)

For LSD to become an accepted microdose treatment, pharmaceutical companies must develop a standard formulation whose dosage can be individualized and that doesn’t degrade over time, as LSD is known to do, Hanka says.

Working with the University of Auckland, MindBio recently completed the first-ever phase-one clinical trial of microdosed LSD, in which 80 healthy participants took either an oral version of the drug or a placebo every three days for six weeks. Early results of this small study, not yet published but shared exclusively with National Geographic, showed the LSD boosted energy, happiness, social connection, and creativity, according to a battery of psychological tests. Plans are underway to test people with major depressive disorder next year.

No one expects all the compounds being tested to pan out, but if even a small number proves valuable, they could make a huge dent in the intractable problem of mental health. “There’s such a huge possibility to improve society,” Enveric’s Tucker says. “Collectively, this whole sector has the potential to bring several hugely impactful new medicines forward.”

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