Can psychedelics treat depression? Maybe, and maybe you don’t even have to make a trip

Robitussin has been a staple in American pharmacies since the late 1940s — but since the 1960s, people have recreationally swallowed bottles of the cough medicine because, at a high enough dose, the active ingredient, dextromethorphan, can cause hallucinations (so-called “robot ripping”). Now that ingredient, found in many cough medicines, has a potential new use: as an antidepressant.

In recent years, studies have shown that conventional antidepressants are only marginally more effective than biologically inactive placebos. Meanwhile, major pharmaceutical companies do very little research into mental health drugs. That’s why researchers and patients have pinned their hopes on psychedelic drugs commonly considered hallucinogenic, such as psilocybin or LSD. Yet evidence of their effectiveness as an antidepressant comes from small studies, one of the largest, involving only 233 people – and no national drug regulator has formally approved them for this use. Against this backdrop, a legitimate pharmaceutical company has quietly taken dextromethorphan from robot ripping to a legally approved depression treatment — but with a major twist.

Axsome Therapeutics, headquartered in New York, markets a drug called Auvelity, which combines dextromethorphan with a drug that reverses hallucinations. After reviewing the evidence for Auvelity’s effectiveness, the US Food and Drug Administration (FDA) approved the treatment in August 2022. with the company expanding its sales network as the number of prescriptions increases. It therefore offers a challenging answer to the hotly debated question that concerns psychedelic medicine: is tripping necessary or useless?

“People need to trip to achieve therapeutic results,” says Robin Carhart-Harris, professor of neurology and psychiatry at the University of California, San Francisco. He prefers to use the word “trip” rather than “hallucination” to describe the experience that follows taking psychedelics such as psilocybin or LSD.

Researchers in several labs have shown that the intensity of the trip when using psychedelic drugs is “probably the strongest predictor” of improved symptoms in conditions such as depression, Carhart-Harris says. But if the FDA approval process worked for Auvelity, it appears to disprove Carhart-Harris’ claim.

Tripping may be helpful for some patients, but it may be too risky for people whose mental health is precarious, or simply too expensive or inconvenient for most people. David E Olson, professor of chemistry and neuroscience at the University of California, Davis, says tripping can help in some cases. “For some patients in certain indications, an in-depth subjective experience can be very helpful and helpful,” he says.

Still, Olson thinks it’s unlikely that every patient needs such an experience to get better. This is important because safely administering psychedelic-assisted psychotherapy requires multiple healthcare professionals, which is expensive and complex. “Very few patients will benefit from this,” he says.

So is it necessary to stumble over? Auvelity accidentally tested that question, because the drug’s conception was not related to robot ripping. The company decided to take action based on evidence from animal testing that dextromethorphan might work as an antidepressant. It has never worked as an antidepressant in humans before because our bodies metabolize dextromethorphan quickly.

The chemical normally produced during metabolic breakdown is a hallucinogen, making it the main cause of robot trips. So Axsome scientists added a second drug, buproprion, to slow that metabolism. By stopping that process, Auvelity does not cause a trip, so patients can safely take the trip at home, without supervision. Buproprion itself is also an antidepressant, so when Axsome did human testing, the clinical trials gave half Auvelity and the other half buproprion alone – confirming that the combination with dextromethorphan works better.

Axsome has shown that this combination can treat major depressive disorder (MDD), also known as clinical depression, diagnosed after at least two weeks of profound low mood. In clinical trials of 1,100 people, the company saw no hallucinations and no one exhibited “drug-seeking behavior.” Public database data shows that approximately 72,000 patients received Auvelity in the US in 2023. The company has not publicly announced plans to seek approval for the drug elsewhere in the world.

Although Auvelity is currently the only prescription treatment for depression with deliberately suppressed hallucinogenic properties, another could soon follow suit. On May 6, NRx Pharmaceuticals, based in Wilmington, Delaware, announced the results of a clinical trial in 91 people for a similar dual action. Based on these findings, NRx will seek FDA approval for a treatment for bipolar depression.

The treatment for NRx is based on a drug better known for treating tuberculosis, D-cycloserine. In that context, it can cause psychosis as a side effect. The symptoms are sometimes called hallucinations, but Jonathan Javitt, the company’s chairman and chief scientist, calls them “wild thoughts.”

Preventing such symptoms is especially important in patients who are suicidal. Even common, non-hallucinogenic antidepressants known as selective serotonin reuptake inhibitors (SSRIs) have sparked controversy for potentially causing suicidal thoughts in some patients. But like Auvelity, NRx’s trip blocking isn’t entirely intentional. It combines cycloserine with a drug already used to treat bipolar depression called lurasidone. “To our knowledge, we have never reported a case of psychedelic effects,” says Javitt. The recent study results showed that the combination treatment alone showed similar efficacy to lurasidone in treating depression, but reduced the side effect of agitation linked to suicidal thoughts, known as akathisia, by 70%.

Taking away these treatments not only means they are easier and safer to take – it could also help solve the puzzle of how they work. Olson explains that psychedelic drugs appear to be effective for illnesses such as depression, post-traumatic stress disorder and substance use disorders. Each disease is related to dysfunction in a part of the brain called the prefrontal cortex.

Olson calls the prefrontal cortex “a master regulator,” which connects to other brain areas that regulate functions including mood, motivation, anxiety, reward and memory. Almost every antidepressant seems to promote the growth of neurons in the prefrontal cortex, Olson says. “Even traditional antidepressants like SSRIs tend to do this,” he adds. “They’re just really bad at it.”

Within 24 hours of someone taking psychedelics, the neurons in a patient’s prefrontal cortex grow rapidly. “We think this is an underlying neurobiological effect that is very important,” says Olson. He adds that with psychedelics, the dose of drug taken correlates with the amount of neuron growth. This is why the intensity of the trip can correlate with improved symptoms, he argues. But his team and other researchers have also shown that drugs can promote neuron growth without hallucinations.

Olson co-founded a pharmaceutical company, Delix Therapeutics, based in Boston, Massachusetts, to exploit this idea. It offers a trip-free treatment for MDD in the early stages of human trials. Olson notes that eliminating the trips also solves a major problem in conducting such studies, which compare the drug to an inactive placebo. With conventional psychedelics, patients can tell if they are tripping. If you don’t get it and you were hoping to get it, it can make you feel worse through a phenomenon called the nocebo effect, Olson explains.

But even if the trips prove unnecessary, psychedelic drugs can illuminate the black box of mental health. “Part of the problem is that I don’t think we really understand mental illness,” says Carhart-Harris. “Psychedelic therapy may be able to address the root causes, allowing people to better understand how they became ill and what it may take to truly get better and stay better.”