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Can psychedelics treat depression? Maybe, and you might not even have to take a trip

The use of the drugs in treating low mood has sparked debate, not least about the necessity of a hallucinogenic experience. But a new discovery may provide an answer

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Robitussin has been a staple of American pharmacies since the late 1940s – but since the 1960s, people have swigged bottles of the cough medicine recreationally because, at a high enough dose, its active ingredient, dextromethorphan, can cause hallucinations (so-called “robotripping”). 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 marginally more effective than biologically inactive placebos. Meanwhile, big pharmaceutical companies conduct very little research into mental health drugs.

So researchers and sufferers have instead placed their hopes in psychedelic drugs usually considered hallucinatory, such as psilocybin or LSD. Yet the evidence of their effectiveness as an antidepressant comes from small trials, one of the largest involving just 233 people – and no national government medicine regulator has formally approved them for this use. Against this backdrop, a legitimate drug company has quietly moved dextromethorphan beyond robotripping into a, legally approved depression treatment – but with an important twist.

Axsome Therapeutics, headquartered in New York, markets a drug called Auvelity which combines dextromethorphan with a drug that negates the hallucinations. After reviewing evidence for Auvelity’s efficacy, the US Food and Drug Administration (FDA) approved the treatment in August 2022, with the company expanding its sales network as prescriptions multiply. In doing so, it offers a challenging answer to the fiercely debated question at psychedelic medicine’s heart: is tripping necessary, or unhelpful?

“People need to trip 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.

Is the therapeutic potential of hallucinogens risky and overhyped?

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 such as depression, Carhart-Harris says. Yet if the FDA approval process has worked for Auvelity, it seems to refute Carhart-Harris’s assertion.

Tripping might benefit some patients, but it could be too risky for people whose mental health is precarious, 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 tripping could help in some cases. “For some patients in certain indications, a profound subjective experience might be really useful and beneficial,” he says.

Yet Olson thinks it’s unlikely that every patient needs such an experience to get better. That’s important, because safely administering psychedelic-assisted psychotherapy demands several healthcare professionals, which is expensive and complex. “Very few patients are going to benefit from that,” he says.

So, is the need for tripping over? Auvelity has tested that question by accident, as the drug’s conception was unrelated to robotripping. The company decided to act on clues from animal tests that dextromethorphan might work as an antidepressant. It has never previously worked as an antidepressant in people because our bodies metabolise dextromethorphan quickly.

The chemical normally produced by the metabolic breakdown is hallucinogenic, making it the main cause of robotrips. So Axsome scientists added a second drug, buproprion, to slow down that metabolism. Stopping that process means Auvelity doesn’t trigger a trip, so patients can take it safely at home, without supervision. Buproprion is also an antidepressant in its own right, so when Axsome did tests in people, the clinical trials gave half of them Auvelity and half 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 in 1,100 people, the company saw no hallucinations, and no one showed “drug-seeking behaviour”. Data from public databases shows 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 else in the world.

While Auvelity is the only currently prescribed depression treatment with deliberately suppressed hallucinogenic properties, another could soon join it. On 6 May, 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 be seeking 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”.

Preventing such symptoms is particularly important in patients who are suicidal. Even common, non-hallucinogenic antidepressants known as selective serotonin reuptake inhibitors (SSRIs) have attracted controversy for possibly causing suicidal thoughts in some patients. But like Auvelity, NRx’s trip-blocking is not wholly 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 trip out of these treatments not only means that they’re easier and safer to take – it might help resolve the puzzle of how they work. Olson explains that psychedelic drugs seem to be effective in illnesses such as depression, post-traumatic stress disorder and substance-use disorders. Each illness is linked to dysfunction in a part of the brain called the prefrontal cortex.

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

You’ve heard of the placebo effect – but what’s the nocebo effect? Is pain all in the mind?

Within 24 hours of someone taking psychedelics, the neurons in a patient’s prefrontal cortex grow rapidly. “We think that that is an underlying neurobiological effect that is really important,” Olson says. He adds that in 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 it’s possible for drugs to promote neuron growth without hallucinations.

Olson has 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 big problem with running such trials, which are supposed to compare the drug with an inactive placebo. With conventional psychedelics, patients can tell whether they’re 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.

Yet even if the trips prove to be unnecessary, psychedelic drugs may be illuminating the black box of mental health. “Part of the problem is that I think we haven’t really understood mental illness,” Carhart-Harris says. “Psychedelic therapy might be able to get at root causes, enable people to better understand how they’ve fallen ill, and what might be required for them to really get better and stay better.”


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