In November 2021, when the psychedelics company Compass Pathways released the top-line results of its trial looking at psilocybin in patients with treatment-resistant depression, the stock of the company plunged almost 30 percent. The dive was reportedly prompted by the somewhat-middling results of the research—but also because of the scattering of serious adverse events that occurred during the trial.
Amid the psychedelic renaissance, bringing up their potential harms has been somewhat of a taboo. The field, vilified for decades, has only just recently reentered the mainstream, after all. But as clinical trials get bigger—and the drugs are increasingly commercialized—more negative outcomes are likely to transpire. With the Compass trial results hinting at this, arguably now’s the time to open up the dialog about psychedelics’ potential adverse effects—even if it means tempering the hype that has built up.
Those results, now published in full in the New England Journal of Medicine, represent the largest randomized, controlled, double-blind psilocybin therapy study ever done. The participants—233 of them, across 22 sites in 10 countries—were split into three roughly equal groups. One group received 1 milligram of COMP360, Compass’s synthetic psilocybin, a dose so low it served as the placebo. The next group received 10 mg and the last group 25 mg. Psychological support was also offered alongside the treatment.
The results were promising, if not painting the picture of a miracle cure. In the 25 mg group, 29 percent of patients were in remission after three weeks compared to just 8 percent in the placebo group. After time, the positive effects waned: After 12 weeks only 20 percent of the high-dose patients were still responding—an improvement over the placebo group that wasn’t statistically significant.
At the same time, 179 of the 233 patients in the trial reported at least one adverse event, like headaches, nausea, fatigue, or insomnia—uncomfortable, sure, but not a huge cause for concern. But 12 patients experienced serious adverse events. These were defined as displays of suicidal ideation, including self-harm. Five of the patients in the highest-dose group were reported to have displayed suicidal behavior, as well as six in the 10 mg group. This was compared to just one in the placebo group.
“Is this expected in a trial like this? To some degree, yes,” says Natalie Gukasyan, assistant professor and medical director for the Johns Hopkins Center for Psychedelic & Consciousness Research. When you’re working with a patient group as vulnerable as those with treatment-resistant depression, higher rates of suicidal ideation are to be expected. But it’s worth noting, she says, that there were higher rates of these events in the higher-dose group, which brings up the question of whether the drug played a role. One thing she thinks would have been helpful to include in the study was the lifetime history of previous suicide attempts in the participants, which is an important predictor of future suicidal behavior.
But given the general reticence to dwell on psychedelics’ downsides, the fact that Compass was upfront about the adverse events is a good thing, says Joost Breeksema, a PhD candidate who studies patient experiences of psychedelics at the University Medical Center Groningen in the Netherlands. In August 2022, Breeksema published a review that looked at how adverse events in psychedelics research have been flagged, and found that they have been inconsistently and probably underreported. Many of the trials Breeksema looked at reported no adverse effects whatsoever—an unlikely reality. The Compass Pathways research “reported adverse effects more rigorously than many of the other trials in our systematic review,” he says.
Though Bd swept through Central America from the 1980s to the 2000s, the analysis that demonstrated its effect on human health could be accomplished only recently, says Michael Springborn, the paper’s lead author and a professor and environmental and resource economist at UC Davis. “The data existed, but it wasn’t easily obtainable,” he says. Over the years, though, county-level disease records were digitized at the ministries of health in Costa Rica and Panama, providing an opportunity to combine that epidemiology in a particular statistical model with satellite images and ecological surveys revealing land characteristics and precipitation, as well as with data on amphibian declines.
“We always thought if we could link [the die-off] to people, more people would care,” Lips says. “We were pretty sure we could quantify changes in bugs, or frogs, or the water quality, or fish or crabs or shrimp. But making that connection to people was so difficult, because the effect was so diffuse, and it happened across such a large area.”
But precisely because Bd swept through Central America in a specific pattern, from northwest to southeast—“a wave that hit county after county over time,” Springborn says—it created a natural experiment that allowed the researchers to look granularly at Costa Rica and Panama before and after the fungal wave arrived. In the health records, they could distinguish that malaria rates were flat in counties (called cantons or distritos) before the Bd fungus tore through, then began to rise afterward. At the peak of the disease surge, six years from the arrival of Bd in an area, malaria cases rose five-fold.
And then they began to fall off again, beginning about eight years after the lethal fungus arrived. Researchers aren’t sure why, because most amphibian populations haven’t bounced back from the fungal onslaught. Though some populations appear to be developing resistance, most have not recovered their density or diversity. Since the fungus lingers in the environment, they remain at risk.
There’s a missing piece in the researchers’ analysis, which is that there is no contemporaneous data to prove that mosquito populations surged in a way that promoted malaria. The surveys they needed—of mosquito density during and after Bd’s arrival, in the 81 counties in Costa Rica and 55 in Panama—simply don’t exist. That makes it difficult for them to determine why malaria fell off again, particularly since frog populations haven’t revived. Springborn theorizes it might be due to human intervention, like governments or organizations noticing the malaria spike and spraying insecticides or distributing bed nets. Or it might be that ecosystems recovered even though the frogs did not, with other predator species taking advantage of the emptied niche to keep mosquito counts down.
But the fact that malaria rates came back down again doesn’t invalidate the findings’ importance. “For the most part, Bd has been a story of the consequences for amphibians, basically: Isn’t it too bad to lose this charismatic group of organisms?” says James P. Collins, an evolutionary ecologist and professor at Arizona State University. (Collins has some connection to this research; he oversaw a grant that the National Science Foundation made to Lips in the 1990s.) “It’s been an embedded assumption that reducing the world’s biodiversity is bound to be harmful. Connecting the dots to real implications for humans is a nice piece of evidence for understanding the consequences.”
The Covid-19 pandemic is considered by many experts to be a mass disabling event. Though most people fully recover from a battle with the highly infectious coronavirus, a significant chunk of patients develop lingering, sometimes debilitating symptoms—aka long Covid. Estimates of how many Covid patients endure long-term symptoms vary considerably. But the US Centers for Disease Control and Prevention recently estimated that nearly one in five Covid patients report persistent symptoms. With hundreds of millions of Covid-19 cases reported around the globe, even the more modest estimates still suggest that tens of millions have lasting effects.
Yet, as those patients seek effective care, researchers are scrambling to define, understand, and treat this new phenomenon. Many patients have reported uphill battles for finding care and relief, including long waits at clinics and few treatment options when they see a care provider.
Cue the quacks. This situation is ripe for unscrupulous actors to step in and begin offering unproven products and treatments—likely at exorbitant prices. It’s a tried-and-true model: When modern medicine is not able to provide evidence-based treatment, quacks slither in to console the desperate, untreated patients. Amid their sympathetic platitudes, they rebuke modern medicine, scowl at callous physicians, and scoff at the slow pace and high price of clinical trials. With any ill-gotten trust they earn, these bad actors can peddle unproven treatments and false hope.
There are already reports in the US of such unproven long-Covid treatments, such as supplements, vitamins, infusions, fasts, ozone therapy, and off-label drug prescribing. But, a British investigation published this week highlights a growing international trend of pricey “blood washing” treatments.
The investigation, carried out by the British outlet ITV News and The BMJ, revealed that thousands of long-Covid patients are traveling to private clinics in various countries—including Switzerland, Germany, and Cyprus—to receive blood filtering, or apheresis, which is not proven to treat long Covid.
Apheresis is an established medical therapy, but it’s used to treat specific conditions by filtering out known problematic components of blood, such as filtering out LDL (low-density lipoprotein) in people with intractable high cholesterol, or removing malignant white blood cells in people with leukemia.
In the case of long-Covid patients, it seems apheresis treatments are used to remove a variety of things that may or may not be problematic. That includes LDL and inflammatory molecules, a strategy initially designed to treat people with cardiovascular disease. Internal medicine doctor Beate Jaeger, who runs the Lipid Center North Rhine in Germany and has started treating long-Covid patients, touts the method, which involves filtering blood through a heparin filter. She also prescribes long-Covid patients a cocktail of anticoagulant drugs.
Jaeger hypothesizes that the blood of people with long Covid is too viscous and contains small blood clots. She suggests that thinning the blood with drugs and apheresis can improve microcirculation and overall health. But there’s no evidence that this hypothesis is correct or that the treatment is effective. When Jaeger tried to publish her hypothesis in a German medical journal, it was rejected.
Robert Ariens, professor of vascular biology at the University of Leeds School of Medicine, told The BMJ and ITV that the treatment is premature. For one thing, researchers don’t understand how microclots form, if apheresis and anticoagulation drugs reduce them, and if a reduction would even matter for disease. “If we don’t know the mechanisms by which the microclots form and whether or not they are causative of disease, it seems premature to design a treatment to take the microclots away, as both apheresis and triple anticoagulation are not without risks, the obvious one being bleeding,” Ariens said.
Jaeger, meanwhile, defended treating patients despite a rejected hypothesis and a lack of evidence. She expressed anger over “dogmatism” in medicine and claimed to have treated patients in her clinic who arrived in wheelchairs but walked out. “If I see a child in a wheelchair suffering for a year, I prefer to treat and not to wait for 100 percent evidence,” she said.
And Jaeger isn’t alone; other clinics have also started offering apheresis for long Covid. The British investigation interviewed a woman in the Netherlands, Gitte Boumeester, who paid more than $60,000—nearly all her savings—for treatment at a new long-Covid clinic in Cyprus after seeing positive anecdotes online. The woman, desperate for relief from her long-Covid symptoms, signed a dubious consent form filled with spelling mistakes, grammatical errors, and half-finished sentences that waived her rights.
Daniel Sokol, a London barrister and medical ethicist, said the form would be invalid under English and Welsh law. “You can’t say, ‘By the way, you agree not to sue us if we cause you horrible injury or kill you, even if it’s through our own negligence,’” he told the investigators. “You can’t do that.”
At the Cyprus clinic, Boumeester received a battery of other unproven treatments along with the apheresis, including vitamin infusions, hyperbaric oxygen treatment, anticoagulants, and hydroxychloroquine, which is notoriously ineffective against Covid-19. After two months in Cyprus, subjecting herself to various treatments and draining her bank account, Boumeester said, she’d seen no improvement in her debilitating symptoms, which include heart palpitations, chest pain, shortness of breath, and brain fog.
“I do think they should emphasize the experimental nature of the treatments more, especially because it’s so expensive,” Boumeester said. “I realized before I started that the outcome was uncertain, but everyone at the clinic is so positive that you start to believe it too and get your hopes up.”
This story originally appeared on Ars Technica.
Allison Guy was having a great start to 2021. Her health was the best it had ever been. She loved her job and the people she worked with as a communications manager for a conservation nonprofit. She could get up early in the mornings to work on creative projects. Things were looking “really, really good,” she says—until she got Covid-19.
While the initial infection was not fun, what followed was worse. Four weeks later, when Guy had recovered enough to go back to work full-time, she woke up one day with an overwhelming fatigue that just never went away. It was accompanied by a loss of mental sharpness, part of a suite of sometimes hard-to-pin-down symptoms that are often referred to as Covid-19 “brain fog,” a general term for sluggish or fuzzy thinking. “I spent most of 2021 making decisions like: Is this the day where I get a shower, or I go up and microwave myself a frozen dinner?” Guy recalls. The high-level writing required for her job was out of the question. Living with those symptoms was, in her words, “hell on earth.”
Many of these hard-to-define Covid-19 symptoms can persist over time—weeks, months, years. Now, new research in the journal Cell is shedding some light on the biological mechanisms of how Covid-19 affects the brain. Led by researchers Michelle Monje and Akiko Iwasaki, of Stanford and Yale Universities respectively, scientists determined that in mice with mild Covid-19 infections, the virus disrupted the normal activity of several brain cell populations and left behind signs of inflammation. They believe that these findings may help explain some of the cognitive disruption experienced by Covid-19 survivors and provide potential pathways for therapies.
For the past 20 years, Monje, a neuro-oncologist, had been trying to understand the neurobiology behind chemotherapy-induced cognitive symptoms—similarly known as “chemo fog.” When Covid-19 emerged as a major immune-activating virus, she worried about the potential for similar disruption. “Very quickly, as reports of cognitive impairment started to come out, it was clear that it was a very similar syndrome,” she says. “The same symptoms of impaired attention, memory, speed of information processing, dis-executive function—it really clinically looks just like the ‘chemo fog’ that people experienced and that we’d been studying.”
In September 2020, Monje reached out to Iwasaki, an immunologist. Her group had already established a mouse model of Covid-19, thanks to their Biosafety Level 3 clearance to work with the virus. A mouse model is engineered as a close stand-in for a human, and this experiment was meant to mimic the experience of a person with a mild Covid-19 infection. Using a viral vector, Iwasaki’s group introduced the human ACE2 receptor into cells in the trachea and lungs of the mice. This receptor is the point of entry for the Covid-causing virus, allowing it to bind to the cell. Then they shot a bit of virus up the mice’s noses to cause infection, controlling the amount and delivery so that the virus was limited to the respiratory system. For the mice, this infection cleared up within one week, and they did not lose weight.
Coupled with biosafety regulations and the challenges of cross-country collaboration, the security precautions required by the pandemic created some interesting work constraints. Because most virus-related work had to be done in Iwasaki’s laboratory, the Yale scientists would take advantage of overnight shipping to fly samples across the country to Monje’s Stanford laboratory where they could be analyzed. Sometimes, they would need to film experiments with a GoPro camera to make sure that everybody could see the same thing. “We made it work,” Monje says.
Spector sees this current version of the Zoe app as a giant citizen science project. Users can sign up to different studies, which involve answering questions through the app. Current studies include investigations into the gut microbiome, early signs of dementia, and the role of immune health in heart disease. Before the pandemic, recruiting hundreds of thousands of people for a study would be nearly impossible, but the Zoe app is now a huge potential resource for new research. “I’d love to see what happens when 100,000 people skip breakfast for two weeks,” says Spector.
People who reported Covid symptoms aren’t automatically included in these new studies. Some 800,000 people have agreed to track their health beyond Covid through the Zoe app, while a smaller proportion of people have signed up to specific trials. But it’s hard to imagine these huge sign-up figures without the app having played such a prominent role during the pandemic.
“These emergency situations become catalysts and create a very unique environment,” says Angeliki Kerasidou, an ethics professor at the University of Oxford. “Something we need to be thinking a bit more carefully about is how we use these situations and what we do with them.”
There’s also a question about the line between providing care and conducting research, Kerasidou says. At the height of the pandemic, the National Health Services of Wales and Scotland directed people to track their symptoms through the Zoe app. Tracking Covid symptoms that way might have seemed like the socially responsible thing to do, but now that the app’s emphasis is on wider health tracking and clinical studies, should people feel the same obligation to take part?
The German app Luca is undergoing an even more dramatic about-face. In spring 2021, 13 German states had signed contact-tracing contracts with the app, worth a total of €21.3 million ($22.4 million). Back then, people would use the app to check into restaurants or other businesses by scanning a QR code. If they crossed paths with someone who shortly afterward tested positive for the virus, the app would tell them to isolate.
But as Germany’s vaccination rates improved, state contracts began to evaporate. In response, Luca’s CEO, Patrick Hennig, looked around for a new business model. In February 2022, Luca revealed it would transform into a payments app, with its new payments function launching in early June.
This was a bold business decision in notoriously cash-friendly Germany. Around 46 percent of Germans still prefer to use cash, according to a 2021 study by British polling company YouGov, compared to just over 20 percent in the UK. But Hennig is hoping to change entrenched habits by leveraging the Luca brand—and user base of 40 million registered people—that the company has built throughout the pandemic.
The idea is that people can use Luca as an alternative to card terminals. At the end of a meal, restaurant-goers scan a QR code that shows them their bill and enables them to pay through the Luca app, using either Apple Pay or their card details. Hennig is attempting to incentivize restaurants to use his system by undercutting the 1–3 percent fee they’re usually charged for using a card terminal. Right now, Luca is free for restaurants and shops to use, but that will shift to a 0.5 percent fee at the end of the year, Hennig says. Over 1,000 restaurants and shops have signed up so far.