Psychedelics as pharmacotherapeutics for substance use disorders: A scoping review on clinical trials and perspectives on underlying neurobiology
Lucas M Wittenkeller, Gary A. Gudelsky, Theresa Winhusen, Davide Amato
British Journal of Pharmacology September 2, 2025 DOI: 10.1111/bph.70181 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Scoping review Peer reviewed |
|---|---|
| Population | Rats (for microdialysis studies); human clinical trials (for SUD treatment) |
| Interventions | Psilocybin MDMA |
| Topics | Addiction MDMA Psilocybin |
| Keywords | Hallucinogen Dopamine Nucleus accumbens Clinical trial Pharmacology |
| Citations | 3 |
| Key findings | High-dose psilocybin produced a sustained mild increase in extracellular dopamine in the nucleus accumbens of rats, suggesting a potential role in restoring dopamine homeostasis relevant to substance use disorders. |
Abstract
Abstract Psychedelics have garnered great attention in recent years as treatments for major depressive disorder (MDD) and treatment‐resistant depression because of their ability to alter consciousness and afflicted cognitive processes with lasting effects. We aimed to characterise how psychedelics are currently being investigated to treat substance use disorders (SUDs). Additionally, we aimed to summarise the available literature on the dopaminergic consequences of classic psychedelics in the nucleus accumbens (NAc), a foundational component of SUDs, to understand how psychedelics may be therapeutically relevant for SUDs from a neurobiological perspective. Two scoping review approaches adhering to PRISMA‐SCR guidelines were conducted. The first screened for ongoing clinical trials utilising psychedelics for SUD treatment registered at ClinicalTrials.gov . The second screened for in vivo microdialysis studies measuring psychedelic‐induced changes in extracellular NAc dopamine in rats, found using PubMed, SCOPUS or Google Scholar. Thirty‐four unique clinical trials were identified targeting alcohol, cannabis, cocaine, methamphetamine, nicotine, and opioid use disorders and mostly consisting of open‐label trials lacking placebo‐treated controls. The most common SUD investigated was alcohol use disorder (AUD). Following stringent exclusion criteria, four publications were identified that measured extracellular dopamine in the NAc following systemic administration of psilocybin or 3,4‐methylenedioxymethamphetamine (MDMA). A sustained mild increase of dopamine was observed that was unique to high‐dose psilocybin. In addition to known therapeutic mechanisms of psychedelics, findings herein suggest that psilocybin may support dopamine homeostasis through restoration of tonic dopamine levels.
Comparable studies
Other preclinical and animal studies on MDMA for addiction, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Reinforcing Effects of MDMA (‘Ecstasy’) in Drug-Naive and Cocaine-Trained Rats Rats | 2001 | Experimental study | |
| Neurotoxic Effects of MDMA on Brain Serotonin Neurons: Evidence from Neurochemical and Radioligand Binding Studiesa Rats and rhesus monkeys | 1990 | Review | |
| Enhancement of conditioned place preference response to cocaine in rats following subchronic administration of 3,4-methylenedioxymethamphetamine (MDMA) Male Sprague-Dawley rats | 2000 | Experimental study | |
| Contribution of impulsivity and novelty-seeking to the acquisition and maintenance of MDMA self-administration Rats | 2012 | Observational cohort | |
| Profile of MDMA Self-Administration from a Large Cohort of Rats: MDMA Develops a Profile of Dependence with Extended Testing Rats | 2012 | Observational cohort | n = 128 |
Citations in the library
Cited by 5
- Policy Considerations for Psychedelics in Research and Medicine – What’s Next on the Schedule? Journal of Science Policy & Governance July 2, 2026
- The mushrooming of the psychedelic renaissance: A scoping review identifying trends in ongoing clinical trials Research Square January 12, 2026
- Perceptions of Psychedelic Decriminalization: Findings from a Community Survey of People Who Use Psychedelics Social Sciences August 23, 2026
- Psychedelics and Reward Processing: Before and After the 1970 Controlled Substances Act Psychedelic Medicine July 24, 2026
- Emerging therapeutic opportunities for psychedelic and related drugs. British Journal of Pharmacology July 1, 2026
Cites 84
- Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder JAMA Psychiatry November 4, 2020
- Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin Proceedings of the National Academy of Sciences January 23, 2012
- Psilocybin-assisted treatment for alcohol dependence: A proof-of-concept study Journal of Psychopharmacology January 13, 2015
- Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. New England Journal of Medicine November 3, 2022
- Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action Neuroreport December 1, 1998
and 79 more in the library