By Deborah Borfitz

September 2, 2025 | A resurgence of research interest in psychedelics over the past 25 years might soon see compounds like psilocybin, otherwise known as “magic mushrooms,” finally having their day. In the clinical trial setting, dozens of studies are now underway testing psychedelics for the treatment of post-traumatic stress disorder (PTSD), depression, and, perhaps most commonly, substance abuse disorders (SUDs). 

In scoping reviews on clinical trials for SUDs and their underlying neurobiological mechanism (accepted for publication by British Journal of Pharmacology, preprint version in MedRxiv), University of Cincinnati (UC) researchers summarized current studies registered at ClinicalTrials.gov and identified rebalancing of the brain’s dopamine system as the means by which psychedelics might help blunt drug-seeking behavior and promote drug abstinence. Study findings, together with an overview on the history of psychedelics, were the subjects of a talk by Davide Amato, Ph.D., associate professor of pharmaceutical sciences, as part of the summer speaker series of UC College of Medicine Center for Addiction Research. 

Amato was joined by Jon Kostas, executive director of the Association for Prescription Psychedelics, who made history as the first to complete a randomized controlled trial of psilocybin-assisted therapy for alcohol abuse disorder at New York University (NYU), which helped him achieve sustained recovery from his treatment-resistant alcoholism. He went on to launch Apollo Pact, a patient advocacy organization focused on raising awareness in advancing psychedelic science and helping others find and navigate clinical trials. 

Psychedelics have been used since ancient times in the East, both for the purpose of healing and various religious and spiritual rituals, Amato says. Aztec populations were also known to use psilocybin mushrooms to induce hallucinatory visions. But their potential therapeutic effects were not historically well appreciated. 

Greater scientific understanding of psychedelics emerged from research at the end of World War II, notably with the 1938 discovery of lysergic acid diethylamide-25 (LSD-25) by the Swiss chemist Albert Hofmann, Amato shares. LSD was termed a psychedelic once the word was coined in 1956 by British psychiatrist Humphry Osmond, pairing two Greek words meaning “mind-revealing.” 

As has been more recently discovered, psychedelics can “uniquely alter perception, cognition, and mood” by eliciting often colorful and detailed visions that affect a person’s sense of self, he continues. While these psychedelic experiences are reversible, “awareness of reality is often preserved.” 

Psilocybin is perhaps most famous for eliciting “mystical experiences where patients feel spiritually connected to the universe,” Amato says. But psychedelics were stigmatized in the 1960s due to confusion over how to define these drugs. 

Some termed psychedelics “psychotomimetics,” implying they mimicked psychosis, says Amato. This was subsequently replaced by the term “hallucinogens,” which was still misleading. 

“In the context of psychosis, altered perception is very different,” he explains, and often involves visual hallucinations that induce terror and upset. Importantly, psychosis is diagnosed based on several persistent symptoms—including delusions, a loss of adherence to reality, disorganized speech, and a flattening of mood—as is seen with schizophrenia. On the other hand, psychedelic experiences are marked by increased ratings in positive attitudes, mood, and social effects. 

Restart on Trials

Between the 1950s and 1970, psychedelics were being explored as a treatment for substance abuse disorders, Amato reports, among them studies conducted by Osmond and Abram Hoffer on patients with alcoholism in Canada. After a single, high-dose LSD session, nearly half of patients remained sober after one year. 

Despite this “unprecedented success rate,” the study was met with skepticism and backlash because of LSD’s association with antiwar protestors and counterculture. All such research halted under the Controlled Substances Act of 1971 when the psychedelics under study (including LSD as well as psilocybin) were classified as Schedule I drugs. 

But research resumed in 2000, due to the low toxicity and abuse potential of psychedelics being used in research settings, he adds. Notably, in 2018, the U.S. Food and Drug Administration (FDA) granted psilocybin Breakthrough Therapy designation for depression. 

A trio of foundational studies helped reignite interest in the use of psilocybin for addiction, the first in 2014 finding psilocybin-assisted therapy led to sustained abstinence from smoking (Journal of Psychopharmacology, DOI: 10.1177/0269881114548296). A small, open-label study the following year showed its potential in reducing alcohol use (Journal of Psychopharmacology, DOI: 10.1177/0269881114565144) and in 2022 with a randomized controlled, double-blind trial where psilocybin led to fewer drinking days (JAMA Psychiatry, DOI: 10.1001/jamapsychiatry.2022.2096). 

The rationale for the recent scoping review of ongoing trials using psychedelics was to prevent repeating studies already underway, avoid overemphasis on certain drugs or study designs, and accelerate their impact in the real world, says Amato. A literature search turned up 121 registered trials, but after applying exclusion criteria (duplicate trials; lacking psychedelic intervention; lacking classic psychedelic, MDMA (Molly or Ecstasy), or Ibogaine; and lacking SUD-related outcome or measure), 34 clinical trials were characterized. 

The trials were predominantly phase 2 studies, either recruiting or not yet recruiting and being conducted in the United States, and with an expected completion in 2025, he reports. However, researchers outside the U.S. aren’t necessarily obliged to register their trials on ClinicalTrials.gov, and some information in the registry appears to be outdated or behind schedule. 

Most of the 34 trials have a parallel design where participants are being assigned to different treatment groups and were either open-label studies or used quadruple blinding, Amato says. Psilocybin was by far the most used psychedelic and alcohol addiction the most common SUD subtype, followed by opioid addiction. 

The doses used in the trials ranged from 20 to 40 mg (single, repeated, or escalating doses) for psilocybin, 14 to 21 mg/70 kg (single dose) for dimethyltryptamine (DMT), and 80 to 160 mg (repeated dosing, sometimes with booster half-dose after two hours) for MDMA, he says. The primary measures were addictive drug use, comorbid conditions, subjective effects, and neurobiological changes, including brain activity, connectivity, and synaptic density changes in the prefrontal cortex after therapy. 

Unique Considerations

One common problem with psychedelic trials is “functional unblinding,” says Amato, since the psychedelic effects on participants are so obvious. The FDA is also concerned that observed benefits may be derived more from the mystical experience than from the drug’s specific therapeutic action. 

Lower microdoses of psychedelics have been proposed to overcome this potential limitation, he adds, but even partial psychedelic effects can result in unblinding. Other suggestions yet to be fully explored are to use 5-HT2A (serotonin) antagonists to block the psychedelic effects while preserving the benefits, or to develop psychedelic analogs to that end. Responsible research, in any case, requires effective controls so trial results don’t overestimate efficacy. 

Psychedelics come in different varieties, and psilocybin is classified as a classic psychedelic along with LSD (derived from ergot, a fungus that grows on rye and other grains), DMT (extracted from psychotria, a flowering plant in the coffee family), and mescaline (found in peyote cactus). MDMA (synthetic entactogen) and Ibogaine (Tabernanthe iboga plant) are classified as non-classic psychedelics together with ketamine and cannabis. 

Mechanistically, non-classic psychedelics may involve various neurotransmitter systems. Classic psychedelics primarily interact with serotonin receptors in the brain, Amato says, and come in three types: tryptamines, ergolines, and phenethylamines. Psilocybin is a tryptamine.   

Classic psychedelics can induce significant neuroplasticity via serotonin signaling, he explains. That is, they can modify cellular structure to cause long-term adjustments to brain connections, and this can happen via either direct or indirect signaling related to activation of the serotonin receptor.  

Another important feature of classic psychedelics is that they can modulate dopamine in specific brain regions, including the cortex, says Amato. To test a hypothesis that the compounds could rebalance the dopamine level in the brain’s “motivation and reward” center from which addictions spring, Amato and his team conducted their second scoping review on how classic psychedelics impact dopamine transmission. 

Balancing Dopamine 

This second literature search of PubMed, SCOPUS, and grey literature identified three hits (all involving psilocybin) out of an initial pool of 272 publications. Notably, researchers were pleased to see the effects of the psilocybin, in terms of moderating dopamine levels, held steady over 180 minutes, says Amato.  

This contrasts with addictive drugs like cocaine that cause dopamine levels to escalate rapidly and, as PET imaging studies have shown, also significantly alter dopamine transmission in the brain of chronic users, he points out. This has been linked to the development and persistence of addiction and contributes to a higher likelihood of relapse. 

It is widely believed that the severity of addiction is tied to the perpetual loss of dopamine, creating cue-induced relapse to drug use, Amato says. Patients might initially consume drugs to experience the euphoric effects but as the cravings grow, they experience malaise and aversion towards activities or situations that were previously enjoyable—a situation they can only resolve by consuming more of the addictive substance. 

The hope here, he says, is that in people with SUD and low dopamine levels, psychedelics might help bring them back to a normal baseline of the neurotransmitter and stop the cycle of craving. But additional studies still need to happen.  

Firsthand Experience

Jon Kostas, whose treatment-resistant alcoholism was cured by psychedelics a decade ago, could serve as Exhibit A for the merits of this line of research. He was a study participant in a clinical trial researching psilocybin and, as he points out, he had never and has never since used hallucinogenic mushrooms. 

As Kostas tells it, he started drinking at a fairly young age and quickly realized he had a different relationship with alcohol than his friends who could limit their intake to evenings or weekends. “Long story short, I tried pretty much every available treatment that was out there to stop drinking [including AA] ... none of which worked,” he says. In desperation, he tracked down the first-of-its-kind study at NYU. 

It helped that the trial was being conducted in a hospital, albeit in a setting resembling a living room, with two doctors and an entire medical team on standby, says Kostas. The year-long trial involved three psilocybin sessions, and the first one was “nerve-wracking” not knowing what to expect. 

The preparation sessions warned him about what he might experience and how to deal with anything that made him feel scared or uncomfortable. He was to be randomized, in a double-blinded fashion, to either the psilocybin pill or a control (Benadryl). This was followed with a debriefing the next day to learn how he felt, what he experienced, and what if any changes he intended to make going forward, plus four or five weekly cognitive behavioral therapy sessions.   

At each of the psilocybin dosing sessions, he was given an eye mask to wear as well as headphones playing mainly classical music without lyrics, for the first 25 or so minutes before the effects of the psilocybin would be kicking in. He was then asked to lie down on a couch. 

The “hallucinations” he experienced might better be described as daydreaming, Kostas says. “I knew I was in the hospital with the doctors there, but I would see different visuals,” which included a glass wine or liquor bottle in the middle of a desert that suddenly disintegrated into the sand. 

Kostas says that he also had a peaceful “death experience” where he saw himself die, in real time, while lying on the couch with the doctors nearby. Unlike with other drugs, he carries these experiences with him to his day not as flashbacks but profound “revelations.” 

Because of this, he was finally able to look at his disease objectively, including how he had been justifying his drinking and causing his parents unnecessary worry, Kostas says. The psychedelic sessions “amplified and exacerbated” his feelings of guilt and shame, so while he credits them for literally saving his life, he has no intention of going through the experience again. 

“I stopped drinking pretty much right away after my very first psilocybin session, and I haven’t touched psilocybin since or any other drugs for that matter,” says Kostas. “It is really fascinating how my perspective and relationship with alcohol shifted and nothing else really shifted or changed about me; it was really just that.” 

Interestingly, through his work at Apollo Pact, Kostas has learned of others participating in psychedelic clinical trials who have also had death experiences. Some of the diehard alcoholics in the NYU trial have also reportedly been able to have an occasional drink—akin to “playing with fire” in the substance abuse world—but without relapsing, he says. 

Psychedelic clinical trials are currently aimed at a single indication despite the overlap between SUDs, PTSD, and depression, says Kostas, all of which are showing promise in early-phase trials. But the qualification criteria on trials could loosen up as research moves closer to the clinic.  

Studies also, at least for now, exclude people who have previously used hallucinogens recreationally, he says, but not because psychedelics wouldn’t be helpful to them in a therapeutic context. The reasoning is that if they received a placebo, they’d know it, creating a breach of the blinding process.