2026 ECNP Congress

EP01-1012

Psychedelics in the neurobiology of addictive behaviours: from recreational use to therapeutic applications

Cláudio A. Peixoto Pereira — A. Fornelos, F. Varandas Rodrigues, I. Miranda Ramos, A.R. Pereira · ULS Alto Minho, Departamento de Psiquiatria e Saúde Mental, Viana do Castelo, Portugal

2026 ECNP Congress

Introduction

Substance use disorders are characterised by dysregulation of reward processing and impaired behavioural control. Their complexity and heterogeneity underscore the limitations of a single, universal treatment approach, which helps explain the high relapse rates and limited long-term efficacy of current interventions. Emerging therapeutic strategies increasingly target underlying neurobiological mechanisms, particularly neural circuit function and neuroplasticity. Among these, psychedelic-assisted therapy has emerged as a promising approach capable of inducing rapid and potentially sustained behavioural change [1],[2].

Methods

The aim was to synthesise current clinical and translational evidence on psychedelic-assisted therapy in substance use disorders, and to examine its neurobiological mechanisms in relation to clinical outcomes. A structured narrative review of recent clinical trials, meta-analyses and translational studies was conducted, focusing on alcohol, nicotine, stimulant and opioid use disorders. Outcomes included substance use, craving, relapse rates and abstinence. Mechanistic evidence related to neuroplasticity and glutamatergic signalling was integrated.

Results

Psychedelic compounds such as Psilocybin and Lysergic Acid Diethylamide (LSD) have demonstrated clinically meaningful effects across multiple substance use disorders. Historical studies with LSD demonstrated early evidence of significant reductions in alcohol misuse following single-dose administration, with effects persisting for several months [2]. More recently, in alcohol use disorder, psilocybin-assisted therapy has been associated with reductions in heavy drinking days of approximately 26 percentage points from baseline and 14 percentage points compared with placebo, with abstinence rates around 30 percent in follow-up studies [2]. These effects are often accompanied by sustained reductions in craving and improvements in psychological well-being.

In tobacco dependence, a randomised trial demonstrated prolonged abstinence rates of 40.5 percent with psilocybin compared to 10 percent with nicotine replacement therapy, suggesting a clinically meaningful advantage over standard pharmacological treatment [2].

Emerging evidence also suggests efficacy in stimulant and opioid use disorders. In cocaine use disorder, ketamine-assisted therapy has been associated with reduced use, enhanced motivation to quit and dampened cue-induced craving [3]. In opioid dependence, early-phase studies suggest reductions in craving, withdrawal symptoms and relapse risk, although robust outcome data remain limited.

Mechanistically, psychedelics promote neuroplasticity through increased glutamatergic signalling and upregulation of neurotrophic factors, supporting synaptic growth and reorganisation of neural circuits. These changes may enhance cognitive flexibility and facilitate modification of maladaptive reward-related behaviours [4]. Therapeutic efficacy appears to depend on the interaction between pharmacological effects and structured psychotherapeutic support.

Conclusions

Psychedelic-assisted therapy represents an emerging neuroplasticity-driven approach to substance use disorders, although current evidence remains preliminary. Converging clinical and mechanistic findings support a model in which treatment effects are mediated by circuit reorganisation and enhanced plasticity [4]. However, several of these substances present recognised potential for misuse and dependence, which, together with regulatory restrictions and historical stigma, represents a significant barrier to clinical implementation. Larger, well-designed randomised controlled trials integrating clinical, neurobiological and patient-level factors are required to establish efficacy, safety and define their role in clinical practice.

References

  1. Hogea, L., Tabugan, D. C., Costea, I., Albai, O., Nussbaum, L., Cojocaru, A., Corsaro, L., & Anghel, T. (2025). The Therapeutic Potential of Psychedelics in Treating Substance Use Disorders: A Review of Clinical Trials. Medicina, 61(2), 278;
  2. Zafar, R., Siegel, M., Harding, R., Barba, T., Agnorelli, C., Suseelan, S., Roseman, L., Wall, M., Nutt, D. J., & Erritzoe, D. (2023). Psychedelic therapy in the treatment of addiction: the past, present and future. Frontiers in psychiatry, 14, 1183740;
  3. Dakwar, E., Levin, F., Foltin, R. W., Nunes, E. V., & Hart, C. L. (2014). The effects of subanesthetic ketamine infusions on motivation to quit and cue-induced craving in cocaine-dependent research volunteers. Biological psychiatry, 76(1), 40–46;
  4. Ly, C., Greb, A. C., Cameron, L. P., Wong, J. M., Barragan, E. V., Wilson, P. C., Burbach, K. F., Soltanzadeh Zarandi, S., Sood, A., Paddy, M. R., Duim, W. C., Dennis, M. Y., McAllister, A. K., Ori-McKenney, K. M., Gray, J. A., & Olson, D. E. (2018). Psychedelics Promote Structural and Functional Neural Plasticity. Cell reports, 23(11), 3170–3182.