Psilocybin for Cocaine Use Disorder
Using psilocybin for CUD 40 years after Dackis and Gold’s dopamine hypothesis
Updated May 16, 2026 | Reviewed by Davia Sills
At long last, research has shown psilocybin (yes, the psychedelic drug) provides relief for people with long-term cocaine use disorder (CUD). Including older, lower-income men addicted for years, a very difficult group “to crack.” Of course, there are still many questions to answer before FDA approval. But for the past 40 years, no drug has worked very well, if at all, in treating CUD. Until now.
Briefly looking backward, Charles Dackis and I proposed our dopamine deficiency theory of cocaine addiction in 1985, at the height of the crack cocaine epidemic. We argued that cocaine dependence was real and also a disorder of dopamine dysregulation. Cocaine’s blockade of dopamine reuptake, mainly within mesolimbic reinforcement pathways, produced intense reinforcement, craving, and compulsive use. We also noted that without cocaine, people with chronic cocaine exposure complained of a mental state defined by anhedonia , dysphoria, craving, and relapse vulnerability. CUD was not primarily about getting high but instead about self- medication attempts to normalize symptoms like low energy, depression , and cocaine craving, caused by a chronically altered dopamine reward system.
The dopamine hypothesis proved important in understanding cocaine, but also other addictions. It didn’t do very well in helping us to find treatments. Over the next decades, investigators tested bromocriptine, amantadine, L-DOPA, pergolide, bupropion, modafinil , psychostimulants, anticonvulsants, antidepressants , selegiline, disulfiram, topiramate, N-acetylcysteine, and numerous other agents to treat CUD. Placebos often performed better. Nothing worked. Until now.
The randomized clinical trial Peter Hendricks and colleagues just described in JAMA Network Open has generated unusual excitement. It’s not only that psilocybin, a hallucinogen, showed benefit. It’s also the magnitude and durability of the effect.
The study randomized 40 adults with CUD to receive either a single high-dose psilocybin session (25 mg/70 kg) or an active placebo with diphenhydramine, both with structured psychotherapy .
The study group was noteworthy. Unlike many psychedelic studies dominated by affluent, highly educated participants, this sample consisted primarily of economically disadvantaged Black participants with a history of cocaine abuse, many using crack. Hendricks noted the team deliberately avoided the typical psychedelic “weird” population—Western, educated, industrialized, and rich. Instead, his participants had severe long-standing CUD. The intervention combined medication administration with extensive preparation and integration of psychotherapy sessions, making treatment substantially more intensive than medication-only trials.
The outcomes were striking. Compared with placebo, psilocybin recipients had 29 percent more cocaine-abstinent days through six months of follow-up. Thirty percent of the subjects achieved complete abstinence compared with none in the placebo arm. No serious treatment-related adverse events occurred. Importantly, abstinence outcomes were confirmed by participant self-report but also by drug testing during follow-up assessments.
Hendricks summarized the central finding in a recent interview: “We found that psilocybin plus psychotherapy elicits more cocaine abstinence compared to placebo plus psychotherapy.” That statement may sound modest, but in cocaine therapeutics, it is very meaningful. Virtually every major pharmacologic strategy tested over the past four decades has either failed or produced inconsistent and modest results.
Equally important was another observation from Hendricks: “Those who received psilocybin reported more days of abstinence, a greater likelihood of complete abstinence, and longer time to first lapse.” This matters scientifically because some interventions reduce craving but not abstinence. Others produce temporary abstinence without affecting relapse vulnerability. Still others improve treatment retention while not altering drug use. Psilocybin achieved “all of the above.”
Could Psilocybin Treat Many or Most Addictions?
Psilocybin has already shown promise in other addictions.
The CUD responses are surprisingly consistent with other psilocybin-substance use studies: a single or a few high-dose sessions plus structured psychotherapy produced significant benefits. For alcohol addiction, one study found that people who received psilocybin with therapy had fewer heavy-drinking days. For tobacco addiction, a recent study found that people treated with psilocybin plus counseling quit smoking at much higher rates than people treated with nicotine patches plus counseling.
These positive signals in cocaine, alcohol, and tobacco use disorders—along with ongoing NIDA-supported randomized clinical trials in tobacco, cocaine, and opioid use disorder—suggest psilocybin may act on addiction-relevant processes cutting across specific drugs, rather than correcting a single transmitter deficit supporting the single diagnostic category, addiction, and help with polysubstance disorders.
The obvious question is how a single psychedelic experience could produce behavioral changes lasting months after the drug leaves the body. Psilocybin is not a maintenance medication and does not directly block cocaine reward. The leading hypothesis is that it transiently increases neuroplasticity and disrupts rigid addiction-related brain networks, potentially making psychotherapy and behavioral change more effective.
Josh Siegel and colleagues recently showed that psilocybin produces acute, large-scale desynchronization of brain networks, along with more persistent changes involving the default mode network and the hippocampus that may last for weeks. Other studies have reported increased cognitive flexibility and changes in prefrontal-subcortical connectivity after psilocybin exposure.
Why might that matter in cocaine addiction? Cocaine dependence is a rigid network of craving, cue salience, autobiographical memory , shame , compulsive identity , and narrowed future orientation. Cocaine-related patterns become overlearned and difficult to escape.
What psilocybin may do is transiently destabilize those entrenched networks. And during this period of enhanced plasticity, psychotherapy may become unusually effective, allowing new emotional learning, revised self-concepts, and weakening cocaine-linked cues and narratives. In this model, psilocybin is less a direct anti-craving drug than a catalyst for cognitive and emotional reorganization. That helps explain why a pharmacologically brief intervention could potentially produce durable behavioral effects.
The rapid antidepressant effects observed in recent psilocybin studies are relevant here too, because depressive symptoms, anhedonia, suicidal ideation, and hopelessness frequently co-occur with stimulant addiction and contribute to relapse risk.
Still, curing our enthusiasm is essential. Psychedelic research has often been limited by small sample sizes and substantial functional unblinding, as many participants and therapists correctly infer treatment assignment despite double-blind designs. Expectancy effects remain a major methodological concern across the field. In the Hendricks psilocybin study, in particular, confidence intervals were wide, and the psychotherapy protocol was intensive, highly specialized, and difficult to generalize to routine outpatient practice.
But the Hendricks psilocybin study matters because CUD has resisted conventional pharmacologic approaches for over four decades, despite increasingly sophisticated neurobiological models.
The Dackis and Gold dopamine hypothesis remains influential and undoubtedly captured important aspects of cocaine and addiction biology. But psilocybin’s apparent effects suggest CUD may not be reducible solely to neurotransmitter deficits. This new study does not show “psilocybin blocks cocaine reward” like naltrexone blocks opioid reward. It is more likely a time-limited neuroplasticity and network-reset intervention that makes psychotherapy, self-reappraisal, extinction learning, and motivational restructuring unusually potent. Psilocybin may acutely disrupt entrenched cocaine-related network dynamics, increasing cortical or limbic plasticity, allowing psychotherapy to work.
Across cocaine, alcohol, and tobacco use disorders, one or several high-dose psilocybin sessions paired with structured psychotherapy appear capable of producing durable reductions in use. Unlike classic maintenance pharmacotherapies, these interventions may work through transient enhancement of neuroplasticity, emotional learning, and cognitive flexibility rather than continuous receptor blockade. Forty years after the dopamine hypothesis transformed addiction neuroscience , psychedelic-assisted therapy now may force the field to reconsider how subjective experience, network plasticity, and psychotherapy together may interact to produce long-term behavioral change.
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Mark S. Gold, M.D., is a pioneering researcher, professor, and chairman of psychiatry at Yale, the University of Florida, and Washington University in St Louis.
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