Hallucinogenic compounds that activate multiple receptors, found in Colorado River toads, show “promising transdiagnostic therapeutic with rapid and lasting effects” for conditions such as depression and anxiety, new findings show, and you don’t necessarily need to hallucinate to therapeutically benefit from the compounds. 

While much is known about the serotonin 5-HT2A receptor, this study explored a serotonin receptor called 5-HT1A, which is activated by an altered compound made from toad secretions that’s believed to alleviate depression and anxiety without inducing hallucinations.

A new study, “Structural pharmacology and therapeutic potential of 5-methoxytryptamines,” was published last month in the journal Nature.

When sensing danger, Colorado River toads, sometimes native to the Sonoran Desert (Incilius alvarius or Bufo alvarius) release a hallucinogenic compound bufotenin that’s structurally similar to DMT from glands in their skin. The compound is also similar in structure and effects to psilocybin as well. The marine toad (Bufo marinus) and European green toad (Bufo viridis) release similar toxins that can sometimes be poisonous to the touch, but only the Colorado River toad releases compounds considered a true hallucinogen.

A team of researchers from Mount Sinai Hospital and Columbia University in New York explored the potential health benefits of psychedelic compounds from toad secretions, and created a new compound that doesn’t trigger hallucinations. 

“We became intrigued by numerous reports of powerful, unique and life-changing experiences associated with its ritualistic or experimental clinical use, which made us wonder about its therapeutic potential and the underlying mechanisms,” David Lankri, a neuropharmacologist at Columbia University and a co-author of the study, told Gizmodo.

Since it’s structurally similar to psilocybin, and based on evidence showing that psilocybin can treat depression in some people, researchers believe there is therapeutic potential with toad secretions as well. 

Most psychedelics research has explored the drug’s effects on a particular kind of serotonin receptor called 5-HT2A. But the team behind the new study focused on a more obscure serotonin receptor called 5-HT1A, which past studies suggest interacts with the toad toxin.

A New Compound Made from Toads

Smithsonian reports that by slightly modifying the 5-MeO-DMT compound, the researchers created another compound called 4-F,5-MeO-PyrT. This new compound interacts primarily with 5-HT1A, a pathway that appears to offer the same antidepressant and anti-anxiety effects without inducing hallucinogenic trips.

It turns out there are already pharmaceutical drugs that target the same receptor.

“Given that 5-HT is the primary target of approved anxiolytic and antidepressant medications, such as buspirone (BuSpar)  and vilazodone (Viibryd), this receptor may contribute to the reported therapeutic effects of 5-MeO-DMT.”

The effects from psychedelic toad secretion compounds suggest long-term effects in overcoming depression-like states.

“Recent preliminary clinical data suggest that 5-MeO-DMT is a promising transdiagnostic therapeutic with rapid and lasting effects. Our work and previous studies have shown that 5-MeO-DMT has comparable signaling potency and efficacy at 5-HT and 5-HT in vitro, and both receptors contribute to its in vivo pharmacology. In light of previous work showcasing 5-HT-selective agonists that alleviate anxiety-like and depression-like states in preclinical models, we wanted to investigate the role of 5-HT in both psychedelic and therapeutic effects of 5-MeO-tryptamines. Although 5-HT is a validated therapeutic target for several approved medications, including vilazodone and buspirone, the importance of 5-HT agonism to the therapeutic effects of tryptamine psychedelics has not been conclusively addressed.”

High Times reported on the toad using its other name, the Sonoran Desert toad, with glands secreting a venom rich in the hallucinogens 5-MeO-DMT and bufotenin, which invaded Arizona last year when monsoon conditions kicked in for the late summer. They can measure up to 7 inches long and have a low-pitched croak that inevitably serenades the night in multiple states during hot wetter months.

Local news stations in Arizona last year reported a surge in Sonoran Desert toad populations now that the rain has started. 

While some researchers aim to bypass the hallucinogenic effects of the toxin, others are trying to enhance it for recreational use. They are sought after so much, toad secretion harvesting has caused them to be endangered in some areas.

Vice Media’s Hamilton Morris documented the Sonoran Desert toad in detail—calling the toads’ secretion the “most potent psychedelic toad venom on Earth,” which also makes it ideal for medical research. Sonoran Desert toad venom should only be vaped or smoked, InStyle reported. Toad venom is scraped from the glands on the animals and dried into a paste, which is later smoked. “The experience is going to start within 10 to 30 seconds and then you’re going to be physically incapacitated for 20 to 30 minutes,” Alan Davis, a Johns Hopkins psychedelics researcher, previously explained in Johns Hopkins Magazine. 

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A new study published in the Journal of Psychopharmacology found that serotonergic antidepressants like SSRIs and SNRIs can decrease psilocybin’s effects, Psychedelic Spotlight reports. Serotonergic antidepressants are often the first avenue for treating depression and include household names such as Prozac and Zoloft. 

The research, published in June of 2023, comes from an online retrospective survey involving 2,153 people who had taken psilocybin mushrooms while also using an antidepressant and individuals who had used psilocybin within two years after stopping their antidepressants. The 611 respondents who had taken mushrooms alongside an antidepressant reported weaker-than-expected psilocybin effects, as did the 1,542 participants who had ceased their SSRI/SNRI medication. However, what’s notable is that the probability of weakened results was not significantly different between those who had discontinued antidepressants a week before taking shrooms and those who ceased taking their meds three to six months prior. 

The study demonstrates that SNRI/SSRI antidepressants reduce the effects of psilocybin compared to non-serotonergic antidepressants—and that individuals who have stopped antidepressants may experience weaker effects up to three months after discontinuing their medication.

People who take psilocybin, the compound responsible for the hallucinogenic properties of magic mushrooms, have been talking about how antidepressants diminish the experience for years. However, what was, for so long, a discussion kept to music festivals and Reddit boards now has scientific backing. The confirmation comes at a time when psilocybin itself gains traction in the treatment of depression. Back in 2022, COMPASS Pathways unveiled the “largest randomized, controlled, double-blind study of psilocybin therapy ever completed,” which shows “significant” improvements to treatment-resistant depression (TRD) symptoms.

And recently, doctors from the University of Texas MD Anderson Cancer Center in Houston began a trial for psilocybin therapy to treat cancer-related anxiety and depression in patients by “examining the effects of psilocybin for patients with controlled advanced cancer on maintenance therapy experiencing challenges with mental health.” 

While this is applaudable, as too many readers know, one does not need a cancer diagnosis to benefit from taking psilocybin for depression. While depressants like SSRIs can take up to six weeks to start working, psychedelics, such as psilocybin (not to mention ketamine), can reverse the effects of depression quickly and, hopefully, more effectively. As a 2020 study suggests, traditional antidepressants improve symptoms in about an extra 20 out of 100 people. Another study published in 2020 indicates that psilocybin can not only be an effective and quick-acting treatment for major depressive disorder, but more than half of the study’s participants stayed in remission from depression four weeks after treatment. 

As a result, looking at statistics alone, many folks currently taking serotonergic antidepressants may be considering swapping out their Lexapro for psilocybin (which may also be more cost-effective in treating depression). So does one need to wean off their current medication before embarking on a psychedelic healing journey? When one takes two drugs together that both increase serotonin levels, such as an SSRI and MDMA, there is always the risk for serotonin toxicity, or serotonin syndrome, which can happen when drugs increase levels of the neurotransmitter serotonin between nerve cells past a safe level, leading to anything from nausea and anxiety to in rare cases coma and death. The latter, as so many people reading this who have taken psychedelics while on antidepressants can confirm, is pretty unheard of. 

The research on antidepressants lowering the effects of psilocybin says that it’s generally safe to use serotonergic antidepressants pre-psilocybin treatment. However, be aware that SSRIs and SNRIs may not only diminish psilocybin’s effects but can do so for up to three months after stopping the antidepressant medication. So, if you’re on an SSRI or SSNI, it’s okay to try psilocybin for depression, but be aware that you may need three months to experience the full effect of your new medicine. 

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Common genetic variations in a particular serotonin receptor could be responsible for the varying effects psychedelic drugs have on different individuals, according to a recently published study from researchers at the University of North Carolina. The study, which comes at a time of reinvigorated research into the potential therapeutic benefits of psychedelic drugs, could shed light on why the substances seem to have dramatically positive effects for some patients with serious mental health conditions while others find little therapeutic value in the drugs.

Bryan Roth, MD, PhD, led a team of researchers at the University of North Carolina (UNC) to complete the study. The goal of the research was to explore how variations in this one serotonin receptor changes the activity of four psychedelic therapies. The laboratory research in cells showed that seven variants uniquely and differentially impact the receptor’s response to four psychedelic drugs—psilocin, LSD, 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and mescaline. The researchers believe that the in vitro research could be useful for determining appropriate mental health therapies for patients.

“Based on our study, we expect that patients with different genetic variations will react differently to psychedelic-assisted treatments,” said Roth, who leads the National Institutes of Health Psychotropic Drug Screening Program. “We think physicians should consider the genetics of a patient’s serotonin receptors to identify which psychedelic compound is likely to be the most effective treatment in future clinical trials.”

Psychedelics and Mental Health

Research published in 2020 in the journal JAMA Psychiatry found that psilocybin-assisted psychotherapy was a quick-acting and effective treatment for a group of 24 participants with major depressive disorder. A separate study published in 2016 determined that psilocybin treatment produced substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer. And last year, researchers determined that psychedelic users had less stress during lockdowns put in place to control the COVID-19 pandemic.

Prior research has also determined that psychedelic drugs stimulate serotonin receptors in the brain. The 5-hydroxytryptamine receptor, also known as 5-HT2A, is responsible for mediating how a person reacts to psychedelic drugs. However, there are several naturally occurring, random genetic variations that can affect the function and structure of the 5-HT2A receptor. Much of the research into the effect that psychedelics have on mental health is inspired by the effect the drugs have on serotonin receptors, which bind the neurotransmitter serotonin and other similar molecules to help regulate mood, emotions and appetite.

Although they show great promise, psychedelic drugs do not seem to be effective as a treatment for everyone. Dustin Hines, PhD, an assistant professor of neuroscience in the department of psychology at the University of Nevada, Las Vegas, who was not involved in the UNC study, said the research could shed light on why psychedelic therapies work well for some patients while others find little therapeutic benefit from the drugs.

“Genetic variation in this receptor has been shown to influence the response of patients to other drugs,” Hines told Healthline. “While psychedelic therapies can provide rapid and sustained therapeutic benefits for multiple mental health concerns, there are a proportion of patients who fail to respond.”

Hines also noted that differences in mental health conditions from person to person could also contribute to how well patients respond to both psychedelic and more traditional treatments.

“Some individuals with depression may have a genetic predisposition that increases the likelihood that they will experience depression in their lives,” Hines said. “Other individuals facing depression may have more situational or environmental contributions.”

The researchers at UNC noted that the study could help provide insight to clinicians considering psychedelics as a treatment for their patients and called for further investigation.

“This is another piece of the puzzle we must know when deciding to prescribe any therapeutic with such dramatic effect aside from the therapeutic effect,” Roth said. “Further research will help us continue to find the best ways to help individual patients.”

Results of the study were published last week in the journal ACS Chemical Neuroscience.

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