Psychedelic-Assisted Therapy for Substance Use Disorders and Potential Mechanisms of Action

Serotonergic ‘‘classic’’ psychedelics (5-HT2A receptor agonists such as psilocybin, LSD, ayahuasca/DMT and mescaline) were investigated clinically in the 1950s–1960s for a range of psychiatric disorders, including substance use disorders (SUD). Rieser and colleagues note that early LSD trials—while methodologically limited by modern standards—yielded encouraging signals for alcohol dependence and that contemporary pharmacotherapies for alcohol use disorder remain only modestly effective (relapse rates up to 50%). Renewed clinical interest has produced a small set of modern trials and multiple ongoing studies (including registered trials for alcohol, nicotine and cocaine), and two recent small trials report beneficial effects of psilocybin on smoking cessation and alcohol use lasting up to 6 months, though both lacked rigorous controls. This chapter sets out to identify and discuss putative clinical mechanisms by which psychedelics might exert therapeutic effects in SUD, and to translate those mechanisms into implications for psychotherapeutic practice. The investigators frame two central questions: which psychedelic-induced neurobiological and psychological effects are clinically relevant in SUD, and how should psychotherapy be configured to leverage those effects? The authors limit their scope to classic psychedelics unless otherwise noted and emphasise that psychedelics are typically given within a psychotherapeutic framework (pharmacologically-assisted psychotherapy, PAT).

The extracted text presents a narrative, mechanism-focused review rather than a report of a primary empirical study; it does not provide a systematic review protocol, search strategy, inclusion/exclusion criteria, or formal meta-analytic methods. Instead, Rieser and colleagues synthesise evidence from preclinical work (in vitro and animal experiments), human neuroimaging and psychopharmacology studies in healthy volunteers and patient samples, and the limited number of clinical trials and case series in SUD populations. Where relevant, the authors draw on examples from ongoing clinical trials (NCT identifiers are cited in the Introduction) and describe the psychotherapeutic framework used in their own clinical programme. That programme extends the BRENDA approach (a biopsychosocial, motivationally informed intervention used in SUD pharmacotherapy trials) to include psychedelic-specific preparation, an acute dosing session, and multi-session integration. The extracted text details the structure of those visits: an initial medical and behavioural assessment, a preparation visit addressing expectations and intentions, the dosing day with instructions to engage with arising material, and several post-dose visits for debriefing and integration.

Rieser and colleagues organise empirical findings and hypotheses around several candidate mechanisms and report supporting evidence from animal, human experimental, neuroimaging and early clinical studies. Induced neuroplasticity: Preclinical studies in rodents and cell systems show that classic psychedelics promote neuritogenesis, spinogenesis and synaptogenesis, and upregulate markers such as BDNF and immediate early genes; signalling pathways implicated include 5-HT2A, TrkB and mTOR. A pig study reported increased SV2A (a presynaptic density marker) in hippocampus and prefrontal cortex one week after a single psilocybin dose. Functional evidence includes faster extinction learning in mice after low-dose psilocybin and increased dendritic spine formation in medial prefrontal cortex, with some new spines persisting to day 7. Human evidence for increased plasticity is indirect (acute medial PFC glutamate increases; post-acute reductions in glutamate+glutamine in the posterior cingulate cortex), and the authors emphasise that translation to humans remains unproven. Alterations in brain network connectivity: SUD is associated with altered resting-state connectivity (e.g. reduced connectivity in precuneus, insula, visual cortex; dACC–striatum changes in nicotine dependence; salience and default mode network dysregulation in cocaine users). Acutely, psychedelics alter thalamo-cortical connectivity (increased thalamus–sensory coupling and increased effective connectivity to posterior cingulate cortex) and produce synchronisation of sensory areas with desynchronisation of associative regions. Such changes are hypothesised to disrupt rigid information integration and may underlie creative thinking and perspective shifts; a few studies report post-acute connectivity changes up to one month, but long-term effects in clinical populations are not well characterised. Emotion processing: Patients with SUD commonly show poor regulation of negative affect, rumination and impaired decoding of others’ emotions. In healthy volunteers, psilocybin and LSD acutely reduce recognition of negative facial expressions and attenuate amygdala responses to negative stimuli, with one-week persistence reported in some studies. Contradictorily, an increased amygdala response was observed the morning after psilocybin in depressed patients prior to integration work, indicating variability across groups and timepoints. Psilocybin also enhanced autobiographical memory recall in healthy samples. Reward and stress processing: Chronic substance use produces long-lasting reductions in dopamine signalling and decreased responsiveness to natural rewards. Psychedelics may act via serotonergic mechanisms to reduce stress-induced anxiety and attentional bias, thereby lowering craving; clinical reports include reduced withdrawal symptoms and craving following psilocybin-assisted smoking cessation. The authors note the theoretical plausibility of reinstating sensitivity to non-drug rewards but emphasise limited direct evidence. Social connectedness: Preclinical and healthy volunteer work shows increased emotional empathy, prosocial behaviour and reduced feelings of social exclusion after classic psychedelics, sometimes persisting months to a year. Participants in smoking cessation trials reported feelings of love, unity and increased social activity that they linked to sustained abstinence. MDMA (an entactogen, not a classic psychedelic) reopens a social-reward learning window in mice, a potentially analogous mechanism though pharmacologically distinct. Subjective experiences and personal meaning: Mystical-type experiences, insight and heightened self-awareness are frequently reported and have been associated with better outcomes in some SUD studies; for example, mystical experiences correlated with smoking cessation at 6 and 12 months and with drinking changes in an AUD sample. Insightfulness and increased perceived self-efficacy are proposed mediators of lasting change. However, animal data complicate the picture: psilocybin-induced neuroplasticity occurred despite blockade of 5-HT2A-mediated subjective effects in one rodent study, and a non-hallucinogenic 5-HT2A agonist (tabernanthalog) reduced alcohol-seeking in mice, raising the possibility that subjective phenomenology may not be strictly necessary for some therapeutic mechanisms. Therapeutic implementation and psychotherapeutic approaches: The authors review established behavioural treatments for SUD—contingency management (CM), cognitive-behavioural therapy (CBT), motivational interviewing (MI)—and argue how psychedelic-induced mechanisms could synergise with each. They describe their BRENDA-based preparation and integration protocol in detail: initial biopsychosocial evaluation, expectation-setting and intention work, dosing day instructions to engage with arising material, followed by multiple debriefing and integration sessions focused on translating insights into daily-life goals. Dose and dosing regimen: Preclinical dose-dependent effects are reported (e.g. low-dose psilocybin produced faster extinction learning in mice; a dose-dependent decrease in hippocampal neurogenesis with conflicting trends at low doses). Clinical observations include reports that AUD patients showed lower acute subjective effects on mystical experience and hallucinogen rating scales than healthy volunteers, suggesting possible need for higher doses in this population; conversely, anecdotal and preliminary reports exist for microdosing. The authors state that whether single or repeated doses are optimal remains unresolved and that ongoing studies (including their single-dose trial) may help clarify this.

Rieser and colleagues interpret the assembled evidence as supporting multiple, potentially synergistic mechanisms by which classic psychedelics could aid treatment of SUD: induced neuroplasticity may open a learning window for psychotherapeutic change; acute alterations in brain network connectivity may facilitate perspective shifts and creative problem-solving; modulation of emotion, stress and reward circuits may reduce avoidance, rumination and craving; and enhanced social connectedness and personally meaningful subjective experiences may support motivation and adherence to non-drug goals. They position these ideas relative to prior work by noting consistencies with historical LSD treatment signals and with contemporary small-scale psilocybin trials, while emphasising that most mechanistic evidence comes from preclinical or healthy volunteer studies. The authors acknowledge several key uncertainties and limitations explicitly: the translational gap between animal plasticity findings and human clinical outcomes; limited and heterogeneous human neuroimaging data on long-term connectivity changes; variability in acute subjective and neural responses across populations; and the lack of controlled trials that isolate the relative contributions of drug effects versus psychotherapeutic context. Practical implications identified by the authors include tailoring psychotherapeutic protocols to exploit specific mechanisms (for example, pairing psychedelics with CM or extinction-based exposure during a putative neuroplastic window, using MI to capitalise on insight and ‘‘change talk’’, and incorporating behavioural activation to harness increased social motivation). They recommend testing adjunctive technologies such as virtual reality or neurofeedback to shape learning and cue reactivity, exploring group formats or involvement of family members to consolidate social gains, and investigating biomarkers (for example baseline resting-state connectivity) that might predict acute effects and treatment response. Finally, the authors call for empirical research to determine optimal dosing, timing relative to integration work, whether subjective mystical-type experiences are necessary for benefit, and how to personalise treatment—highlighting the need for well-designed controlled trials and evidence-based psychotherapeutic frameworks.

The authors conclude that classic psychedelics show promise as components of pharmacologically-assisted psychotherapy for SUD, provided that mechanistic insights guide the design of psychotherapeutic protocols. They argue for empirically testing targeted combinations (for example, integrating MI, CM, extinction-learning approaches, behavioural activation, and technologies such as VR or neurofeedback) and for resolving outstanding questions around dose, timing, necessity of subjective effects, and predictors of response. If these knowledge gaps are addressed, Rieser and colleagues suggest psychedelic-assisted therapy could mature into an efficacious, evidence-based treatment option for patients with SUD.