A Single Dose of Psilocybin Just Beat Cocaine Addiction. Here's How.

For fifty years, cocaine use disorder has had no approved medication. Not one. Clinicians treating cocaine addiction have worked with behavioral therapy alone, which helps some patients but leaves most untouched. The pharmaceutical industry largely abandoned the problem decades ago after a string of failed trials. The FDA has never approved a single drug for cocaine use disorder.

In May 2026, a randomized controlled trial published in JAMA Network Open changed that picture. Not with a pharmaceutical. With a single dose of psilocybin.

The results were not subtle. Participants who received psilocybin plus cognitive behavioral therapy achieved complete cocaine abstinence at a rate of 30 percent at six months. The placebo group achieved 0 percent. The odds of complete abstinence were 18 times higher in the psilocybin arm. The odds of any cocaine use at 180 days were 72 percent lower. In a field where "some improvement" is the realistic goal, these numbers read like a different category of outcome.

Fifty Years Without a Solution

Cocaine use disorder is not a niche problem. Roughly 24 million people globally use cocaine, and an estimated 14 to 20 percent develop a use disorder. In the United States, cocaine-involved overdose deaths have increased sharply since fentanyl began contaminating the cocaine supply. Emergency departments see cocaine-related visits in the hundreds of thousands annually.

The treatment gap is real. Unlike opioid use disorder, which has three FDA-approved medications — methadone, buprenorphine, and naltrexone — cocaine use disorder has none. Contingency management, a behavioral approach that provides incentives for drug-free urine tests, shows consistent efficacy in clinical settings but is difficult to implement at scale and rarely available outside specialized programs. Cognitive behavioral therapy reduces use in some patients. Twelve-step programs help a subset. But for a substantial share of people with cocaine use disorder, nothing works well enough to produce lasting change.

Researchers have tested hundreds of compounds over the years. Modafinil, disulfiram, topiramate, baclofen, N-acetylcysteine — each has shown some promise in early trials and failed in later ones. The mechanisms are complex: cocaine acts primarily by blocking dopamine, serotonin, and norepinephrine reuptake, producing an intense and brief surge of reward signaling that leaves the brain depleted and craving the next hit. Building tolerance to that cycle pharmacologically, without creating a new dependency, has proved intractable.

That's the context for what Peter Hendricks and his team at the University of Alabama at Birmingham set out to test.

The Study: Design and Population

The trial was randomized, double-blind, and placebo-controlled. Forty participants were enrolled, all meeting criteria for moderate-to-severe cocaine use disorder as defined by the DSM-5. The study ran at UAB in partnership with Johns Hopkins University and Karolinska Institute.

The population is worth dwelling on, because it's not who typically shows up in psychedelic research. Eighty-three percent of participants were male. Median age was 50. Eighty-three percent were Black. Sixty-five percent had annual household incomes at or below $20,000. This is a group that has been systematically excluded from the psychedelic research renaissance — a research literature that has drawn persistent criticism for its reliance on educated, white, higher-income participants, limiting both the generalizability of results and the equity of potential therapeutic access.

Hendricks had made this a deliberate priority in earlier work showing that psilocybin-occasioned mystical experiences predicted reduced cigarette smoking. His cocaine trial continued that commitment.

Participants were randomized to receive either a single oral dose of psilocybin at 25mg per 70kg body weight, or an active placebo of 100mg diphenhydramine (the antihistamine in Benadryl — noticeable but pharmacologically inert with respect to the brain's addiction circuitry). Both groups received the same psychotherapy: four to five preparation sessions before dosing and five integration sessions afterward, all grounded in cognitive behavioral therapy for substance use.

The primary outcomes were cocaine abstinence (confirmed by urine toxicology) at 30, 60, and 180 days.

The Results

At 180 days, 30 percent of psilocybin participants had achieved complete cocaine abstinence, confirmed biochemically. Zero percent of placebo participants had.

The odds ratio for complete abstinence was 18.0 — meaning psilocybin participants were 18 times more likely to be fully abstinent at six months than those who received placebo and therapy. The hazard ratio for any cocaine use across the 180-day follow-up period was 0.28, meaning psilocybin participants had a 72 percent lower risk of any cocaine use at any point in the follow-up period.

Outcomes at 30 days (40% vs 5%) and 60 days (35% vs 5%) followed the same pattern. The effect didn't evaporate as time went on — which has been one of the most consistent and remarkable features of psilocybin research across indication areas. The acute experience seems to do something that persists.

There were no serious adverse events attributable to psilocybin. The most common side effect was transient anxiety during the dosing session, managed by the therapists present. No participants were hospitalized. No clinically significant cardiovascular events occurred.

How Psilocybin Plus Therapy Works for Addiction

The mechanism is still being characterized, but the current understanding draws on several converging lines of evidence.

Psilocybin is converted in the body to psilocin, which acts primarily as a 5-HT2A serotonin receptor agonist. In addiction research, serotonergic systems are less central than dopaminergic ones — which is part of why the results surprised some researchers. But the effects of psilocybin extend beyond direct receptor action.

Neuroimaging studies have shown that psilocybin produces a temporary but pronounced disruption of the default mode network (DMN) — a set of brain regions associated with self-referential thought, rumination, and habitual patterns of mind. Carhart-Harris et al. described this as "ego dissolution" at high doses and demonstrated that the degree of DMN disruption correlates with the intensity of the subjective experience. In addiction, where the DMN is often involved in craving-related rumination and self-narratives that maintain use ("I can't quit," "this is who I am"), temporary dissolution of that network may create a window for therapeutic reorientation.

The mystical experience component also appears to matter directly. Across addiction studies — including the Johns Hopkins smoking cessation trial and multiple alcohol use disorder trials — the subjective sense of awe, interconnectedness, and transcendence correlates with long-term outcomes. Participants who rate their psilocybin session as one of the most meaningful experiences of their lives tend to do better. The therapy structure before and after the session is how that experience gets integrated into lasting behavioral change.

There may also be effects on neuroplasticity — psilocybin has been shown to promote structural changes in neuronal connectivity in preclinical models, which could contribute to the persistence of effects beyond the acute pharmacological window. Whether that mechanism is operative in humans at therapeutic doses remains under investigation.

Limitations and What Comes Next

The study had real limitations. Forty participants is a small sample. With twenty per arm, individual variation has an outsized effect on the statistics, and even a few outcomes either way would shift the numbers substantially. This is a proof-of-concept trial, not a definitive efficacy study.

Blinding was imperfect. A majority of participants correctly guessed which treatment they received, which is essentially unavoidable when one arm involves a psychedelic experience and the other involves an antihistamine. This introduces the possibility that expectancy effects contributed to outcomes — though expectancy alone typically doesn't produce 18x odds ratios over placebo in substance use disorder research.

The lead researcher, Hendricks, also served as one of the therapists — a conflict of interest by design, given his expertise, but one that reviewers noted limits independence. The study was conducted at a single site.

None of these limitations invalidate the findings. They contextualize them: this is a first RCT showing proof of concept, warranting replication in larger, multi-site trials with independent therapists.

That replication process is already underway, partly through commercial channels. Filament Health, a Canadian natural psychedelic drug development company, has licensed intellectual property related to this research and is advancing PEX010, a natural psilocybin product, through Phase 2 trials targeting stimulant use disorder. If larger trials replicate the efficacy signal, PEX010 could become the basis for an FDA submission.

For context on the regulatory pathway: the FDA granted Breakthrough Therapy Designation to psilocybin for treatment-resistant depression in 2018 and to MDMA-assisted therapy for PTSD in 2017 (subsequently rejected in 2024 on manufacturing and study design grounds). Psilocybin for cocaine use disorder has not yet received any similar designation, but the data from this trial would likely support a formal designation request.

What This Means for Treatment

Cocaine use disorder has zero FDA-approved medications. That fact has been true for fifty years, and the pharmaceutical industry has largely stopped trying to change it. The research community working on psychedelic-assisted therapy didn't set out to solve cocaine addiction specifically — the early studies focused on depression, anxiety, and tobacco dependence. But the mechanism, it turns out, may be broadly applicable to compulsive behavior driven by rigid self-narrative and reward dysregulation.

What makes this study particularly significant beyond the numbers is the population. The people in this trial were not the kind of people who typically participate in psychedelic research. They were older, predominantly Black, predominantly low-income. They were people who had been largely invisible in the psychedelic renaissance. The fact that the treatment worked in this population matters for what comes next: a therapy that only works for privileged, white, highly educated patients is not a solution to cocaine addiction as it actually exists in the United States.

The path from a 40-person proof-of-concept to an FDA-approved treatment involves years and tens of millions of dollars in additional trials, manufacturing standardization, therapist training pipelines, and regulatory review. None of that is guaranteed. But after fifty years of nothing, the existence of a randomized controlled trial showing this effect size is a genuinely different starting point.

For anyone following the psychedelic science space, this is among the most significant findings of the decade. The question is no longer whether psychedelics can produce meaningful outcomes in addiction — the data on psilocybin, MDMA, and ibogaine collectively have answered that. The question is how to build the systems that make those outcomes accessible to people who need them most.