When Johannes Reckweg arrived in the Netherlands in 2016 to work on his master’s program in neuropsychology, he didn’t expect to learn about a psychedelic compound commonly found in a toad that lives half a world away. But his research on stimulants led him to another substance that quickly piqued his interest: 5-MeO-DMT.

“It sparked my fascination with this topic of pharmacological or psychopharmacological research and how drugs affect human behavior,” Reckweg said.

While the natural hallucinogen can be found in some plants and fungi, its best-known source is the Sonoran Desert toad, a greenish gray amphibian that roams the southwestern United States and northwest Mexico. To get the psychedelic, poachers squeeze the toad’s glands to secrete a milky toxin that contains 5-MeO-DMT, along with other molecules. Though the toad usually survives this process, conservationists warn that rising demand in the once obscure psychoactive compound has put pressure on the toad population. They call it yet another risk for an amphibian already threatened by dry weather, a shrinking habitat, and disease.

Now, amid a global renaissance in psychedelics as medicine, scientists are working to study and develop synthetic formulations of 5-MeO-DMT for hard-to-treat mental health disorders, including depression, anxiety, and post-traumatic stress disorder. The laboratory formulations seem unlikely to curb recreational toad squeezers, but limited studies suggest that 5-MeO-DMT could have a real medicinal value — though further research needs to be done.

If it proves to be effective, the compound, which stands out for its quick and potent effects, could be a cheaper alternative to psilocybin and LSD, which are longer acting and, so, more expensive to administer.

Conservationists warn that rising demand in the once obscure psychoactive compound has put pressure on the toad population.

“There’s a lot of excitement in the field,” said Anya Ragnhildstveit, the director of research at Pneuma Science’s Center for Psychedelic Research. “I think it has to be dialed back a little bit, just so we can really make sure we’re doing this with the right intentions and taking the time to really understand what’s going on.”

If evidence can definitively show that synthetic 5-MeO-DMT can alleviate the distressing mental health symptoms, Reckweg said, it would be an important treatment option to consider.

No single medication works for everyone, he added, yet there will be patients who will not respond to certain psychedelics, “but they might very well respond to 5-MeO-DMT.”

The compound 5-MeO-DMT was first synthesized in 1936 by Japanese scientists Toshio Hoshino and Kenya Shimodaira — long before it was identified in the toad. “It was just part of explorational chemistry at that stage,” said Rafaelle Lancelotta, a therapist and psychedelic researcher at Ohio State University. “They were not thinking about whether or not this was psychoactive, because that wasn’t something at the time that people were looking at.”

The toad’s own 5-MeO-DMT was first reported in the mid-1960s, but it was a pamphlet published in 1983 that ushered it from obscurity and called attention to the creature’s psychoactive compound. The publication gave instructions on how to extract it, dry it, and smoke it.

The large toad dwelled largely undisturbed until the 21st century. That changed in 2011, after Octavio Rettig, a self-described pioneer of toad medicine and a controversial figure, introduced the psychoactive to an Indigenous tribe in the Mexican state of Sonora, Arizona’s southern neighbor, as a treatment for addiction among members of the fishing community. The practice of smoking the toad toxin soon spread, along with dubious tales of ancestral Indigenous use. (Although toads feature prominently in the iconography and mythology of some Mesoamerican cultures, whether the amphibians have been used in traditional ceremonies for their psychoactive properties is uncertain.)

The laboratory formulations seem unlikely to curb recreational toad squeezers, but limited studies suggest that 5-MeO-DMT could have a real medicinal value.

The same year Rettig introduced 5-MeO-DMT to the tribe, the U.S. government declared the compound to be an illegal substance, much like it did in 1970 with more widely used psychedelic drugs like psilocybin and LSD. The prohibition brought psychedelic research to a near standstill. Several other countries took similar actions, prompting today’s 5-MeO-DMT researchers and recreational users to flock to Mexico, where the toad’s hallucinogenic is still unregulated. The compound is still classified as a Schedule I drug, meaning it’s only legal in the U.S. for research use. Scientists interested in studying the synthetic compound must obtain special permits from the government.

In the Netherlands, where Reckweg first came across 5-MeO-DMT at Maastricht University, he became increasingly intrigued by the data in observational studies performed in natural settings, and by internet reports from underground users who smoked the compound and reported relief from symptoms of depression, stress, and anxiety.

One such study, completed by 24 participants, associated the intensity of psychedelic experiences with lessened depression and stress, as well as increased life satisfaction, in those who smoked the natural toad poison. (While most of the participants reported no underlying mental health conditions, those who said they had such disorders experienced relief.) Meanwhile, most of the 362 participants in an anonymous online survey, published in 2019, linked intense experiences to improved depression and anxiety.

Later that year, Reckweg launched a study investigating the safety and psychedelic effects in a controlled environment — one of the first laboratory studies to administer synthetic 5-MeO-DMT to humans. At that time, he said, “5-MeO-DMT was really, at least in the scientific world, not really looked at that much yet.”

A pamphlet published in 1983 called attention to the toad’s psychoactive compound, giving instructions on how to extract it, dry it, and smoke it.

The trial, published in 2021, involved 22 healthy volunteers who inhaled different doses of a vaporized 5-MeO-DMT formulation. Over the course of 15 to 20 minutes, some participants fell into what seemed like a calm sleep, while others screamed or rolled around on their floor mattresses, their arms flailing. Such responses are not unusual, Reckweg said: “The effects are so strong that the patient or participant is either unconscious or very vulnerable in that moment.”

The drug often produces intense emotional and physical reactions in users, so clinical studies must follow strict safety criteria. In Reckweg’s study, a physician was always present to ensure safety, he said, and there was no need for medical intervention.

After the drug’s effect dissipated, participants told the research team of having “whiteout” feelings, or less visual than vivid memories. Such altered perceptions set 5-MeO-DMT apart from other psychedelics — such as DMT, the psychoactive chemical in the ayahuasca plant — whose reported effects tend to leave more distinct impressions, like the user is flying through space or meeting otherworldly entities, he said.

While that trial established that the drug could be safely administered, Reckweg said that in a subsequent 2023 study, the vaporized synthetic drug reduced symptoms of treatment-resistant depression in 16 patients, eight of whom took increasing doses. After a week, about half of the patients were in remission.

Around that time, 5-MeO-DMT captivated Ragnhildstveit when she learned its impact on a suicidal woman who, after consuming a single dose of the natural compound, experienced quick relief from her chronic PTSD, which stayed in remission for a year afterward. Ragnhildstveit published the woman’s story in 2023 as a case report in the journal Frontiers in Psychiatry. To protect her privacy, she withheld the name of the woman.

“She had tried pretty much every conventional treatment that’s indicated for PTSD – psychotherapy, medication, she even tried cannabis,” Ragnhildstveit said. “She really had done a lot, and nothing was helping her situation.”

The compound also caught the attention of Lancelotta, who has conducted observational studies on the effect of both natural and synthetic forms of 5-MeO-DMT. The researcher’s findings, published in several studies over the past five years, suggest the synthetic compound may potentially bring relief to people, including those suffering from depression, anxiety, and post-traumatic stress disorder.

For example, in one 2019 study conducted in the Czech Republic, where 5-MeO-DMT is unregulated, Lancelotta observed its effect on about a dozen volunteers who inhaled a vaporized synthetic version, guided by a facilitator, in a yoga studio. The researchers found “decreases in different biomarkers related to stress, as well as biomarkers related to inflammation,” Lancelotta said, adding that patients also reported increased life satisfaction after their 5-MeO-DMT experience.

“One of the things that is very promising is that it has a pretty short duration of action, so you can have a profound mystical experience in a short period of time,” Lancelotta said of 5-MeO-DMT. This would significantly reduce time and expense for patients, particularly when compared to other psychedelics that have shown promising therapy; in such a setting, for example, a psilocybin experience could last up to eight hours.

While 5-MeO-DMT is the primary compound in the toad’s milky secretion, also known as bufotoxin, the toad harbors lower amounts of components like bufotenine, a weak hallucinogen. Much of the synthetic research has focused on the psychoactive properties of 5-MeO-DMT, and little is known about how much those other components contribute to the effect. As with other psychedelics, exactly how all the involved mechanisms work is not fully understood.

“The effects are so strong that the patient or participant is either unconscious or very vulnerable in that moment.”

To date, there are no studies explicitly comparing the effects of natural and synthetic versions, said Charles Nemeroff, a physician and chairman of the department of psychiatry and behavioral sciences at the Dell Medical School at the University of Texas at Austin.

But while the toad poison can vary in its concentration of 5-MeO-DMT, the synthetic form offers exact doses of the pure compound. “You know exactly what you’re getting,” Nemeroff said.

Researcher Ryan Khan, who works with Ragnhildstveit at Pneuma Science, said using a synthetic 5-MeO-DMT in research can allow for a clearer assessment of therapeutic effects to produce safety and efficacy data needed to translate the compound into medicine. And there’s also the matter of the amphibian, he said.

Several biopharmaceutical companies are now creating and testing in international clinical trials different synthetic formulations that contain the isolated 5-MeO-DMT molecule. The molecule itself cannot be patented, but companies can claim as intellectual property their own formulations developed for clinical use with a novel route of administration, for example.

While much of the earlier 5-MeO-DMT research involved smaller numbers of participants who were healthy, or who self-reported various mental health symptoms, these larger studies are primarily testing the effectiveness of various formulations in people diagnosed with hard-to-treat depression.

Still in its early stages, research on 5-MeO-DMT appears to be riding the coattails of research into psychedelic drugs for clinical applications that restarted in earnest about two decades ago, carving an incremental path toward a changing legal landscape. In 2018, the U.S. Drug Enforcement Administration streamlined the application process for those interested in researching controlled substances for medical use.

Meanwhile, public support for psychedelics appears strong in the U.S., according to the Center for the Science of Psychedelics at the University of California, Berkeley. In a July 2023 survey, roughly six out of 10 voters favored legalizing therapeutic access to psychedelics. Nearly half supported doing away with criminal penalties for personal use and possession — an emerging trend in several states pursuing psychedelics reform. In late 2020, Oregon became the first state to establish a regulatory framework for psilocybin and to decriminalize personal possession of all drugs. The state, however, recently decided to recriminalize hard drugs.

Buoyed by the initial research into 5-MeO-DMT, biopharmaceutical companies set out to develop patent-protected formulations of the compound for various medical conditions, primarily depression. For regulatory approval of the drug, biopharmaceutical companies must conduct multiple clinical studies.

GH Research, an Ireland-based biopharmaceutical company that funded Reckweg’s 5-MeO-DMT studies, is now testing formulations in more patients with various depressive disorders at clinical trials across Europe. Beckley Psytech, a company based in the United Kingdom, has launched studies to evaluate the psychoactive drug at 40 sites across six countries: Australia, Germany, Poland, Spain, the U.K, and the U.S.

In a July 2023 survey, roughly six out of 10 voters favored legalizing therapeutic access to psychedelics.

The psychedelic revival brought Robert Conley out of a retirement after just a couple of years. A psychiatrist and former chief scientific officer at Eli Lilly, he now works as Beckley’s chief scientific and medical officer. Psychedelics like 5-MeO-DMT “have an important use in human medicine,” he said.

The company’s ongoing trial follows earlier studies with fewer than 20 participants primarily in England. Participants were administered a 5-MeO-DMT formulation that elicited short, profound effects in both healthy participants and people with depression, Conley said. The ongoing trial aims to determine whether “the drug can work, that people tolerate it, and that the effect of the antidepressant improvement actually lasts over a period of time,” he said.

The study, which started in late 2023, aims to administer a patented, special salt formulation of the psychoactive drug via a nasal device to 225 people diagnosed with serious depression. “We will follow them up very actively for about six months after they’re dosed, and then we will follow them a little more loosely if they’ve done well after six months,” Conley said.

A future trial could involve hundreds more participants, but it could be years before it lands in a health care setting due to mandated rigorous clinical trials. And, given the history of psychedelics legislated as drugs of abuse, 5-MeO-DMT must go through a complex process to gain federal approval before it can be used as a therapy.

Ragnhildstveit said she wants to believe that whenever 5-MeO-DMT is ready to fulfill a medical need, it can avoid the rampant, unchecked use in mental health treatment of the anesthetic ketamine, which can induce psychedelic and dissociative effects. “I hope we will have the training in place, and the workforce in place, to make sure that people are having really safe journeys,” she said.

The literature so far has suggested that, in a supported setting, 5-MeO-DMT can offer relief for a short time, Lancelotta said. “But if you are interested in really having that long-term resolution of symptoms and long term-improvement in quality of life, it’s going to require a lot more than simply dosing people with a drug.”

For the past three years, biologists Karla Montaño Pérez and Jesús Salvador Jáuregui Santacruz, through an environmental government agency in Mexico’s Sonora state, have conducted research on the toad and its habitat, as well as launched public education campaigns. “Our job, in addition to the monitoring of the toad, is also to educate people so that they can contribute to its conservation,” Montaño Pérez said in an interview in Spanish.

She and Jáuregui Santacruz try to dispel the notion that squeezing the toad’s glands for the milky substance is harmless, because handling and removing the animal from its habitat can cause undue stress. Toads also are susceptible to chytrid fungus, which has decimated worldwide populations of toads, frogs, and other amphibians. Human handling can spread the lethal pathogen from infected to healthy toads, said.

Whether research into synthetic 5-MeO-DMT might one day help reduce demand for the toad’s natural psychoactive is an open question. “The use of toad-sourced 5-MeO-DMT will always be there,” said Robert Villa, president of the Tucson Herpetological Society in Arizona. He works closely with the Sonoran biologists on toad conservation efforts.

“I hope we will have the training in place, and the workforce in place, to make sure that people are having really safe journeys.”

Meanwhile, much of the early research enthusiasm into the molecule’s therapeutic properties is based on animal or small human studies with limited or no follow-up — uncertainties that also linger around other psychedelics, including MDMA, which the U.S. Food and Drug Administration is considering approving as a treatment for PTSD.

[UPDATE: A day after this story was published, an FDA advisory panel voted against approving MDMA as a treatment for PTSD.]

Still, the early research findings give Reckweg optimism that a fast-acting psychoactive substance could provide a more accessible and affordable medical treatment. “If you can cut down on those costs by having a shorter experience, that would cut down significantly on the costs that are required for both sides, patients and providers,” he said.

Nemeroff, the physician at UT Austin, also finds the shorter-acting 5-MeO-DMT could be particularly appealing for patients. “These are not easy experiences,” he said. “They can be difficult, they can be very mind-altering, and many people have anxiety when they’re having this experience. And so shorter may be better.”

UT Austin recently opened a center for psychedelic research and launched a clinical study, in collaboration with a Mexico treatment center, on how 5-MeO-DMT and psilocybin affect prolonged grief.

“The use of toad-sourced 5-MeO-DMT will always be there.”

“They come to us, and we measure their symptom severity using well-validated scales of depression and anxiety,” Nemeroff said. Once participants undergo brain imaging, they travel to Mexico for treatment with the natural form of 5-MeO-DMT. Upon their return to the U.S., researchers will analyze images of their brain for any changes.

Meanwhile, the case that Ragnhildstveit documented based on the woman’s own data of her experience, gave her impetus to explore the possible benefits of the synthetic psychoactive on anorexia, as well as on trauma in veterans and first responders. “We’re actively working on those right now and really excited to get them out because they’re very different populations, different interventions and dosing,” she said.

For Reckweg, if rigorous studies can prove that the synthetic psychoactive has a lasting therapeutic effect, then it’s “not a question of what we should be using or what we should be looking at.” he said. “So that, for me, plays a very big part in this research — that we put a focus on doing it properly and doing it safely, not only for the participants, but also for the toads.”

This article was originally published on Undark. Read the original article.