June 23, 2024

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

In recent years, studies have found that conventional antidepressants are only slightly more effective than biologically inactive placebos. Meanwhile, big pharmaceutical companies do very little research on mental health drugs. Researchers and sufferers therefore placed their hopes instead on psychedelic drugs that are usually considered hallucinatory, such as psilocybin or LSD. However, the evidence for their effectiveness as an antidepressant comes from small trials, one of the largest involving only 233 people – and no national government medicines regulator has formally approved them for this use. Against this backdrop, a legal drug company has quietly moved dextromethorphan past robotic ripping into a legally approved depression treatment—but with an important twist.

New York-headquartered Axsome Therapeutics markets a drug called Auvelity that combines dextromethorphan with a drug that negates the hallucinations. After reviewing 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 prescriptions increase. In doing so, it offers a provocative answer to the hotly debated question at the heart of psychedelic medicine: is tripping necessary, or unhelpful?

“People have to travel to have therapeutic outcomes,” says Robin Carhart-Harris, a 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 taking psychedelic drugs is “probably the strongest predictor” of improved symptoms in conditions like depression, Carhart-Harris says. But if the FDA approval process worked for Auvelity, it appears to disprove Carhart-Harris’ claim.

Tripping may benefit some patients, but it may be too risky for people whose mental health is uncertain, or simply too expensive or inconvenient for most people. David E Olson, a professor of chemistry and neuroscience at the University of California, Davis, says tripple can help in some cases. “For some patients in certain indications, a profound subjective experience can be really helpful and beneficial,” he says.

Still, Olson thinks it’s unlikely that every patient needs such an experience to get better. This is important because the safe administration of psychedelic-assisted psychotherapy requires multiple health care professionals, which is expensive and complex. “Very few patients are going to benefit from it,” he says.

So is it necessary to stumble? Auvelity accidentally tested that question, since the drug’s conception was unrelated to robotic ripping. The company decided to act on clues from animal tests that dextromethorphan could work as an antidepressant. It has never worked as an antidepressant in humans before because our bodies metabolize dextromethorphan quickly.

The chemical normally produced by the metabolic breakdown is hallucinogen, making it the main cause of robot rip. So Axsome scientists added a second drug, buproprion, to slow that metabolism. Stopping that process means Auvelity doesn’t cause a trip, so patients can take it safely at home, unsupervised. Buproprion is also an antidepressant in its own right, so when Axsome did tests in humans, the clinical trials gave half of them Auvelity and half of buproprion alone – to confirm 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 pervasive low mood. In clinical trials with 1,100 people, the company saw no hallucinations, and no one exhibited “drug-seeking behavior.” Data from public databases show that, in the US in 2023, approximately 72,000 patients received Auvelity. The company has not publicly announced plans to seek approval for the drug elsewhere in the world.

While Auvelity is the only currently prescribed depression treatment with deliberately suppressed hallucinogenic properties, another may soon join it. On May 6, NRx Pharmaceuticals, based in Wilmington, Delaware, announced the results of a clinical trial in 91 people for a similar drug double act. Based on these findings, NRx will seek FDA approval for a treatment for bipolar depression.

NRx’s treatment 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, refers to them as “wild thoughts.”

Prevention of such symptoms is especially important in patients who are suicidal. Even common, non-hallucinogenic antidepressants known as selective serotonin reuptake inhibitors (SSRIs) have attracted controversy because they may have caused 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 the best of our knowledge, we’ve never had a case of psychedelic effects being reported,” says Javitt. The recent trial results showed that the combination treatment showed similar efficacy to lurasidone on its own in treating depression, but reduced the side effect of agitation linked to suicidal thoughts, known as akathisia, by 70%.

Taking the journey out of these treatments doesn’t just mean they’re easier and safer to take — it may help solve the mystery of how they work. Olson explains that psychedelic drugs appear to be effective in illnesses such as depression, post-traumatic stress disorder and substance use disorders. Every disease is linked to dysfunction in a part of the brain called the prefrontal cortex.

Olson calls the prefrontal cortex “a master regulator,” which is connected to other brain regions that regulate functions including mood, motivation, fear, reward and memory. Almost every antidepressant appears to promote neurons growing in the prefrontal cortex, Olson says. “Even traditional antidepressants like SSRIs tend to do this,” he adds. “They are just very bad at it.”

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

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

But even if the trips turn out to be unnecessary, psychedelic drugs can illuminate the black box of mental health. “Part of the problem is that I think we haven’t really understood mental illness,” says Carhart-Harris. “Psychedelic therapy may find the root causes, enable people to better understand how they got sick, and what may be needed for them to actually get better and stay better.”

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