Psilocybin for treating substance use disorders?

De Veen and colleagues frame substance use disorders (SUDs) as prevalent, chronic conditions with high relapse rates despite existing psychological and pharmacological treatments. The introduction emphasises that roughly 50-60% of patients with drug and alcohol use disorders relapse within 6–12 months after treatment and argues that novel interventions that reduce craving and substance use are urgently needed. The authors point to hallucinogens, in particular psilocybin, as a candidate treatment given recent promising findings and its pharmacological actions on serotonin systems implicated in emotion, stress and cognitive control. This narrative review aims to summarise human and relevant preclinical evidence for psilocybin’s therapeutic potential in SUD, and to discuss putative mechanisms of action through receptor systems, brain regions and cognitive and emotional processes. The authors set out to integrate clinical observations (including pilot studies in alcohol and tobacco dependence), neuropharmacology, neuroanatomy and network-level effects to generate hypotheses about how psilocybin might reduce addictive behaviour and inform directions for future research.

The paper is a narrative review rather than a systematic review or meta-analysis. The abstract states the review was based on the search terms "psilocybin, substance use disorder, addiction, depression, serotonin," but the extracted text does not report a full search strategy, databases searched, date ranges, or explicit inclusion/exclusion criteria. Consequently, the methods are limited to a selective synthesis of preclinical and human studies and mechanistic literature rather than a comprehensive, reproducible literature search. Because methodological detail is sparse in the extracted text, it is not possible to state how studies were identified or appraised, nor whether a formal risk-of-bias assessment was performed. The review therefore presents an expert narrative integrating pharmacology, neuroanatomy, animal data and a small number of human clinical reports that have investigated psilocybin in SUD or in related conditions (for example, anxiety and depression in terminal illness) that the authors consider mechanistically informative.

Neuropharmacology and receptor binding: Psilocybin (a prodrug converted to psilocin) has a chemical structure similar to serotonin and binds with high affinity to serotonin receptors, particularly 5-HT2A (reported Ki = 6 nM) and to a lesser extent 5-HT1A (Ki = 190 nM). Pharmacological blockade studies cited in the review show that ketanserin (a selective 5-HT2A antagonist) dose-dependently blocks the psychological effects of psilocybin and that risperidone (5-HT2A/D2 antagonist) can abolish its psychotropic effects, supporting a key role for 5-HT2A signalling in psilocybin’s subjective and behavioural effects. Neuroanatomy and network effects: The review outlines high 5-HT2A receptor densities across cerebral cortex (frontal, parietal, temporal, occipital) and in limbic structures such as the amygdala and paraventricular nucleus (PVN). The authors link receptor distribution to functional systems relevant to SUD, invoking a ‘‘triple network’’ model (default mode network, DMN; executive control network, ECN; salience network, SN). They report that psilocybin can transiently increase cortisol and ACTH, with endocrine elevations returning to baseline within about 5 hours, and that a cortisol spike may activate large-scale networks. The review cites an fMRI study finding decreased amygdala reactivity during acute psilocybin and another report that psilocybin reduced stressor‑induced modulation of amygdala connectivity, which the authors suggest could shift emotional bias away from negative processing. Cognition, flexibility and compulsivity: Animal and nonhuman primate studies are summarised showing enhanced reversal learning (improved behavioural flexibility) after psilocybin or LSD. The authors emphasise that 5-HT2A agonism appears to facilitate behavioural flexibility in orbitofrontal circuits, whereas antagonism impairs it. They propose that improved flexibility and reduced compulsivity could help patients disengage from maladaptive drug-seeking behaviours. Preclinical addiction-related data: Limited animal self-administration data are reported: in one monkey study three of four animals showed low self-administration rates only modestly above placebo and were unable to maintain self-administration behaviour, suggesting low reinforcing potential. The review notes interactions between serotonergic systems and stress (CRF/HPA-axis) that are relevant to stages of addiction (acquisition, maintenance, relapse) and highlights cross-talk between serotonin transporters and CRF signalling in animal models. Human clinical findings in SUD and related disorders: The authors summarise a small number of human studies relevant to addiction. Typical dosing in the SUD studies cited was about 0.3–0.4 mg/kg administered in two to three sessions. A pilot study in alcohol dependence reportedly found significant reductions in percentage drinking days and heavy drinking days with large effect sizes, although precise numerical effect estimates are not provided in the extracted text. A psilocybin-assisted smoking cessation study is cited in which 80% of participants had quit smoking at 6-month follow-up, substantially higher than typical behavioural/pharmacological therapies; participants attributed quitting to changes in future orientation, strengthened self-efficacy and altered priorities. The review also references an epidemiological finding that hallucinogen use predicted reduced recidivism among substance-involved offenders. Safety, metabolism and adverse events: Psilocybin is rapidly dephosphorylated to psilocin after oral administration, distributed to tissues including the brain, glucuronidated and excreted primarily via the kidneys (reported 65%) and to a lesser extent via liver and intestine (15–20%). The review stresses generally low toxicity in animal and human studies, with mainly mild physiological effects such as transient hypertension and tachycardia. Two reported fatalities are noted in the extraction: one after ingestion of a very large dose producing psilocybin plasma levels of about 4 µg/mL and another in a heart transplant recipient with reported psilocin levels of about 30 µg/mL; however, the authors state it is unclear at what plasma concentrations severe toxic effects occur. Prolonged psychosis after a single dose is described as extremely rare and typically associated with pre-existing vulnerability. The risk of dependence on psilocybin appears very low: users develop rapid tolerance, and reports indicate little evidence of craving or withdrawal. The review quotes historical estimates for prolonged psychiatric symptoms after LSD (0.08–0.09% in healthy volunteers, 0.18% in psychiatric patients) but stresses that careful screening, set and setting and session support reduce risks.

De Veen and colleagues interpret the assembled evidence as supporting a plausible role for psilocybin in treating SUD, mediated by two broad mechanisms: (1) amelioration of negative emotional states and stress via 5-HT2A/1A receptor effects on amygdala and HPA‑axis function, and (2) enhancement of cognitive flexibility and reduction of compulsivity through effects on prefrontal and orbitofrontal circuitry and on large-scale networks (SN, DMN, ECN). They argue that these neurobiological and cognitive changes could reduce craving, improve control over emotional responses to drug cues and facilitate behavioural change necessary for recovery. The authors position these findings against earlier psychedelic research (including mixed results for LSD in alcohol dependence) and recent small, promising trials with psilocybin in alcohol and tobacco dependence. They caution that many existing studies lack double-blind, placebo-controlled designs and have small sample sizes, limiting the strength of causal inference. The review therefore calls for well-designed, placebo-controlled randomised trials with larger samples to confirm efficacy. Key limitations acknowledged include the small number of clinical SUD studies to date, lack of long-term relapse data (6–12 month relapse outcomes are generally missing), and limited mechanistic clarity about how 5-HT2A signalling modulates network dynamics in SUD. The authors also highlight uncertainties about whether psilocybin’s efficacy differs by substance class (for example psychostimulants versus opiates), how genetic variation in 5-HT receptors or pre-existing personality/trait characteristics might moderate response, and whether sex/gonadal hormones and HPA‑axis status influence outcomes. They recommend preclinical work on self-administration and reinstatement paradigms, longer-term human follow-up studies, investigation of interactions with existing behavioural and pharmacological treatments, and careful study of safety in adolescents if preventive applications are considered. Looking ahead, the authors expect growth in psychedelic research and encourage qualitative work to understand subjective processes by which psilocybin-assisted interventions support recovery. They reiterate that despite low physiological toxicity and low addictive potential, rigorous controlled trials are required before psilocybin can be implemented clinically for SUD.

The authors conclude that psilocybin is a promising candidate for further research as a treatment for substance use disorders. They hypothesise that anti-addictive effects may arise from modulation of negative emotional states and stress, together with improvements in cognitive inflexibility and compulsivity, mediated largely via 5-HT2A and 5-HT1A receptor activity. Given the limited number of published clinical studies and methodological shortcomings in much of the historical literature, De Veen and colleagues emphasise the need for more extensive, controlled research to determine efficacy, safety, interactions with existing treatments, and underlying mechanisms before psilocybin could be considered for clinical implementation in SUD care.