Could psilocybin therapy hold the answers for treating anorexia?

Anorexia nervosa is a heartbreaking disease not only for patients and their families, but also for the clinicians and researchers trying to help them. Fewer than half of anorexia patients fully recover, and 1 in 5 never improve at all. Anorexia has the highest mortality rate of any psychiatric disorder, with a suicide rate 18 times higher than the general population. For the professionals guiding anorexia patients toward recovery, it can feel like there aren’t enough tools at their disposal. 

Anorexia is typically characterized by food restriction and an obsession with weight. People with anorexia adhere to strict self-imposed rules around eating to prevent weight gain. Finishing a plate of food, for example, might be a daunting task for someone with the disorder. While talk therapy and certain medications can help, no drugs have been specifically FDA-approved for the estimated 2 million Americans who will develop the eating disorder in their lifetimes. 

And that’s if patients even make it to treatment. People with anorexia, about 75% of whom are women, are often reluctant to seek the early interventions that can save their lives. Many do not want treatment or are unable to recognize they need it. That’s because weight gain, the inevitable result of rehabilitation, can be terrifying for someone with anorexia – even those who want to recover may be too anxious to follow through. 

“It’s difficult to get people with anorexia to come to treatment because there’s so much ambivalence and ambiguity about recovery,” says Stephanie Knatz Peck, a clinical psychologist at the University of California, San Diego who specializes in eating disorders.

But Knatz Peck is experiencing something very different with her current avenue of research. She is testing the use of psilocybin, the psychoactive compound in “magic mushrooms,” as a treatment for anorexia. Their initial trial was small, involving just 10 patients, but the early results are encouraging, Knatz Peck says. Four out of the 10 participants showed improvement after a three-month follow up – a promising result for a small psychotherapy trial. 

“One thing that we’ve also been struck by is the number of people with anorexia that have really been interested in the study,” says Dr. Walter Kaye at UC San Diego ’s Eating Disorders Center who is Knatz Peck’s co-investigator. Many participants came to the study after trying other available treatments with little to no success, according to Kaye. “They’re searching for new answers,” he says. 

Anorexia patients may see psilocybin therapy as a less daunting treatment option, says Thomas Hildebrandt, a psychologist and anorexia expert at Mount Sinai Hospital in New York. Psilocybin has no weight-gain side effects and is a temporary treatment, meaning that patients can eventually stop receiving psilocybin treatments if they achieve recovery. This makes it an attractive option for patients who are apprehensive about traditional treatments that hinge on refeeding, explains Hildenbrandt, which is a time consuming strategy he likens to chemotherapy. “What we’re asking patients to do to recover is to consume a large amount of something that they feel is almost like a poison,” he explains. 

Hildebrandt thinks psychedelic therapy is different. “What we should be doing instead of trying to relieve symptoms is that we should really be trying to enhance learning,” he says.

Psychedelics may do just that. Research suggests that these drugs help people who are stuck in a particular mode of thinking change their mindset. They do this by stimulating neuroplasticity, which is the brain’s ability to build and reorganize synaptic connections in response to learning. For anorexia patients, this rewiring may help them develop a healthier perception of eating. 

Kaye and Knatz Peck are looking specifically at serotonin, an important neurotransmitter that regulates neuroplasticity. Serotonin carries messages between the brain’s nerve cells and plays an important role in several key components of anorexia: mood regulation, anxiety and eating behavior. 

For years, eating disorders were considered a symptom of societal pressures to be thin. This pressure may play a role, but developments in brain-imaging technology have allowed clinical psychologists to investigate the biological drivers of anorexia as well. Neuroimaging has revealed strong evidence that anorexia stems, at least in part, from an irregularity in the brain’s serotonin production, Kaye says. 

“One of the earlier studies we did was to look at levels of serotonin in cerebrospinal fluid,” he says. Kaye’s previous research found that actively ill anorexia patients had low levels of serotonin in their spinal fluid compared with healthy individuals. But after long-term recovery from anorexia, patients showed higher than average levels. 

These findings suggest that the pre-anorexic brain produces too much serotonin. But why, then, did actively ill anorexia patients show reduced serotonin levels? It may be because they were malnourished, Kaye explains. Serotonin synthesis begins not in the brain, but in the gut. The secret ingredient for making serotonin is tryptophan, an amino acid we can only get from the food we eat.

Kaye hypothesizes that people with anorexia may subconsciously restrict their food intake to lower their above-average serotonin levels. His study linked overactive serotonin production to high anxiety and obsessive behavior. Starvation may allow anorexia patients to control these symptoms by restricting their tryptophan intake, thus limiting the amount of serotonin they can produce. 

But as patients continue to starve themselves, their brains respond by building more serotonin receptors to efficiently use what little serotonin remains. This creates a vicious cycle where the anorexia patient needs to starve themselves further and further to control their anxiety, according to Kaye’s research. 

So, he and Knatz Peck began looking for a way to correct overactive serotonin production that doesn’t involve food restriction. Enter psilocybin, which induces its effects on the brain by targeting a serotonin receptor called 5-HT2A. Masquerading as serotonin, it binds to the receptor, but elicits only a fraction of the anxiety response that serotonin binding does. They suggest psilocybin might disrupt that viscous cycle: it stops the brain from building excess serotonin receptors by tricking it into thinking there’s plenty of serotonin available. 

Knatz Peck and Kaye’s serotonin hypothesis is what’s driving their clinical trial sponsored by COMPASS Pathways, a London-based drug company that has developed its own psilocybin formulation, COMP360, and enlisted the two San Diego researchers to assess its safety and efficacy for anorexia patients. Their research team recently started recruiting participants for the second phase of the clinical trial. The treatments would not be widely available for at least several more years, however, and only if much more extensive testing yields strong results.

Scientists still don’t fully understand the link between serotonin pathways and anorexia. “We know little bits and pieces,” says Dr. Natalie Gukasyan, a psychiatrist at Johns Hopkins University who is also researching psilocybin treatment for anorexia. While neuroimaging studies have provided some clues, Gukasyan points out that there are challenges to studying the anorexic brain this way.

“Imaging can be confounded by things like nutritional status,” she explains. Malnourishment may not only affect serotonin pathways, but also other aspects of brain structure and functioning. 

“All this is to say that there’s not a great slam dunk,” she says. Serotonin pathways may not tell the whole story about what is happening in the anorexic brain. 

Other experts in the field are watching with interest and skepticism. “I think just because something’s new doesn’t mean we should dismiss it, but it also doesn’t mean that because it’s new, it’s gonna save us,” Hildebrandt says. At this early stage, he adds, it’s impossible to tell whether psilocybin will be a game changer for anorexia patients. In psychiatry in general, “medications that work well, consistently, without unwanted side effects are really hard to find,” Hildebrandt says. 

“If there was a safe and effective pharmacological treatment, that would be amazing,” says Kristen Portland, executive director of the National Association of Anorexia Nervosa and Associated Disorders, a support organization that connects anorexia patients with treatment resources. But, she adds, “like everything to do with eating disorders, there’s no sweeping answer.” Although psilocybin could become a useful treatment option for clinicians to add to their arsenal, it may not yield improvements for every patient. Six of the ten participants from Kaye and Knatz Peck’s initial trial did not show clinically significant improvement in disordered eating behavior. 

The COMPASS Pathways study is just one of several clinical trials that could offer more insight. From the initial results, “we’ve certainly been struck by changes in perception of some people,” says Kaye. In the second phase, Kaye and Knatz Peck will expand their trial to 60 anorexia patients. One study group will receive 1-milligram doses of psilocybin while another will get much higher 25-milligram doses. The researchers will compare the two groups to assess differences in the safety and efficacy of the drug.

Phase 2 of the trial could provide further evidence that psilocybin diminishes anorexia symptoms, but the researchers won’t know for about another year when the study is complete. “It’s very difficult to say anything when we’ve only studied 10 participants,” Knatz Peck says. 

A successful drug treatment for anorexia would be a breakthrough, says Portland of the national anorexia support group. She points out that standard practice for eating disorder treatment often involves a multidisciplinary team of professionals, including therapists, dieticians, psychiatrists and physicians providing care in a residential facility. “That can be very expensive,” Portland says. It can also require a huge investment of time from patients who may have little to spare. “It’s incredibly difficult for a lot of folks to do that, especially older people with jobs, kids, families.” 

Will outpatient psilocybin treatment someday present a solution to these problems while also making the road to recovery less intimidating by helping patients overcome their fear of weight gain? Kaye and Knatz Peck think it eventually might – but only if years of additional testing involving larger groups of patients are successful.  

 Mount Sinai’s Hildebrandt, who is not involved in the clinical trial, thinks it’s an idea worth pursuing. His anorexia patients, he says, would benefit from more options – and more reasons for hope. “The clinician in all of us – I’m not alone in this – is never satisfied until we can help absolutely everyone get back to the life they want to lead,” he says.