Psychedelics as an emerging novel intervention in the treatment of substance use disorder: a review

Psychedelics are serotonergic compounds that alter perception, cognition and consciousness and commonly produce mystical-type experiences. After an early period of intense clinical interest followed by decades of regulatory restriction, clinical research with classical psychedelics (defined largely by agonism at the 5-HT2A receptor) has re-emerged. Divito and Leger frame this resurgence against the public-health burden of substance use disorders (SUD), noting rising overdose deaths, large numbers of people using illicit drugs and major global mortality from tobacco and alcohol, and they argue that existing pharmacotherapies for many addictions leave considerable room for improvement. This review aims to appraise the current state of evidence on psychedelic pharmacology and the clinical literature concerning their use in SUD, alcohol use disorder (AUD) and smoking cessation. The authors also examine proposed neurobiological mechanisms—particularly effects on mesolimbic reward circuitry, cortical networks and the default mode network (DMN)—and they highlight gaps in the evidence base and priorities for future research.

The extracted text presents this article as a narrative review rather than a systematic review or meta-analysis conducted by the authors themselves. The paper synthesises findings from preclinical work, open-label trials, surveys of self-administration, some randomised controlled trials (RCTs) from the literature and a cited prior meta-analysis. The authors discuss mechanistic neurobiology alongside clinical outcomes across substances. The extracted text does not clearly report a formal search strategy, eligibility criteria, dates or databases searched, nor does it present a standard risk-of-bias assessment or meta-analytic methods performed by the review authors. Consequently, the methods for study identification and selection are not described in the provided extraction. Instead, the review integrates animal studies, small RCTs, observational and survey data, and earlier meta-analytic findings to build a narrative about mechanisms and clinical effects. Where trial features are discussed, the authors reference study designs from the cited literature (for example RCTs, open-label trials and surveys) and draw on both clinical and neuroimaging investigations to link subjective effects to neural targets. No pooled statistical methods or original quantitative synthesis by the review team are reported in the extracted text.

Neurobiological findings reviewed by the authors address three broad neural domains. In the mesolimbic pathway, psychedelics interact with serotonergic receptors located in structures such as the ventral tegmental area (VTA) and nucleus accumbens (NAc). Preclinical studies cited show that selective 5-HT2A agonists can potentiate or modulate accumbal dopamine release during psychostimulant exposure (for example DOI potentiation of cocaine-associated dopamine release in rodents) and that 5-HT2A antagonists (ketanserin) can attenuate some of these effects. The review also cites experiments showing very rapid tachyphylaxis to 5-HT2A agonists after single doses in animals, and the authors hypothesise that rapid tolerance might blunt pathological 5-HT2A-driven potentiation of reward circuitry. Cortical effects focus on high 5-HT2A expression in layer V pyramidal cells and the claustrum. Activation of 5-HT2A receptors in cortex is linked to glutamatergic signalling, altered gene expression, upregulation of plasticity-related factors (for example increases in c-fos and brain-derived neurotrophic factor in prefrontal cortex in rodents) and to a cortical state described as desynchronisation or increased entropy. The authors present these changes as allowing disruption of maladaptive top-down control and enabling new cognitive patterns that could be therapeutically relevant in SUD. Regarding the default mode network (DMN), human neuroimaging studies are reported to show acute reductions in DMN activity and increased global functional connectivity after psychedelic administration. Specific findings cited include LSD-induced decreases in DMN activity that correlated with subjective openness and psilocybin-related decoupling of medial prefrontal cortex (mPFC) and posterior cingulate cortex (PCC), which was associated with ego-dissolution and persistent positive attitude changes at follow-up. Small trials are also reported to show transient increases in cortisol and adrenocorticotropic hormone after some psychedelic administrations. The subjective phenomenon of mystical-type experience is discussed as a putative mediator of enduring clinical benefit in some trials, but the authors note conflicting evidence because microdosing—sub-perceptual dosing commonly used outside clinical settings—has been reported by some self-report surveys to yield benefit despite lack of overt mystical experiences. Controlled evidence for microdosing is limited; the review cites an RCT using 13 µg LSD that showed dampened amygdala activity and altered limbic connectivity, and a prospective self-report study (n=98) that found reduced mind-wandering among microdosers. Clinical outcome data summarised are heterogeneous in design and quality. Historical and recent studies report positive signals for multiple substances. A cited meta-analysis of 536 patients across six RCTs found a single dose of LSD reduced alcohol misuse and increased abstinence lasting 6–12 months. Psilocybin trials combined with psychotherapeutic support are described as reducing drinking days and cravings; ayahuasca has been associated with remission in some systematic reviews. Large online surveys of self-administering individuals are reported to show substantial retrospective reductions in AUD and SUD criteria post-use (examples: in one survey of 343 self-administrators 72% met AUD prior to use and 83% no longer met AUD criteria after; in another of 444 self-administrators 96% met SUD criteria prior and 27% met criteria after). Microdosing surveys reported cessation rates and reductions in use (for example 15.9% cessation and 42.1% reduction in alcohol use; 14.4% cessation and 29.5% reduction for other substances), though these data are self-reported and uncontrolled. Smoking cessation outcomes are emphasised as particularly promising. An intervention combining psilocybin with cognitive behavioural therapy reportedly produced 67% abstinence at 1 year, compared with typical pharmacotherapies that generally yield < 35% abstinence at 1 year. Uncontrolled survey data of self-administered psychedelics among smokers reported abstinence and reductions in daily use (reported rates of 38% abstinence and 28% reduction in daily use). The authors also note long-term persistence in some cohorts, citing reports of about 60% abstinence at 30 months after a psychedelic session and anecdotal reports of positive behavioural changes extending beyond 25 years. Safety data described in the review indicate that adverse effects are dose-dependent and that the most common acute adverse reaction is transient anxiety or dysphoria (“bad trip”). Serious reactions such as prolonged psychosis and suicide attempts are reported as rare, with rates cited of approximately 0.8 and 1.2 per 1000, respectively. The authors stress, however, that many of the positive clinical findings derive from small, open-label, or self-report studies and that larger, blinded RCTs are comparatively few.

Divito and colleagues interpret the assembled evidence as supportive of a multipronged mechanism through which psychedelics may ameliorate addictive behaviours: modulation of mesolimbic reward circuitry, induction of cortical plasticity and disruption then re-integration of maladaptive DMN-driven self-referential processes. They argue that these neural effects—anchored by 5-HT2A receptor agonism—could explain single-dose and sustained behavioural changes reported across substances, and they posit that the subjective mystical-type experiences may, in some studies, mediate enduring therapeutic benefit. The authors position these findings within the broader literature by noting both historical positive reports (dating to the 1950s) and more recent controlled and imaging studies that provide convergent mechanistic and clinical signals. Nevertheless, they emphasise heterogeneity in the evidence base: many early and contemporary studies are small, open-label or rely on uncontrolled, retrospective self-report. Where RCT data exist (for example the cited LSD trials in AUD, and specific psilocybin smoking cessation trials), results are encouraging but limited in scale. Key limitations acknowledged include the review’s reliance on a literature that is disproportionately represented by non-randomised designs, the small sample sizes of many trials, and the uncontrolled nature of survey data. The extracted text also notes that some mechanistic findings (for example cortisol/CRF increases) appear paradoxical relative to subjective reductions in negative affect and that further research is required to clarify these complexities. Importantly, the review does not present a formal risk-of-bias assessment of the included studies in the extracted text. For clinical and research implications, the authors call for rigorous future investigation: larger, blinded, randomised clinical trials; more detailed characterisation of dosing strategies including microdosing versus full psychoactive doses; and translational work to parse how different neural targets contribute to observed behavioural outcomes. They suggest that, if replicated in robust trials, psychedelics could become mainstream adjuncts for treating tobacco, alcohol and other substance use disorders because of their potential for long-lasting effects after only one or a few administrations.

The authors conclude that psychedelic compounds, administered in controlled clinical settings and appropriate dosages, have the potential to produce persistent, generally favourable effects for patients with substance use disorders, with serious adverse events being uncommon. They restate their central hypothesis that therapeutic effects derive from modulation of multiple neural networks (mesolimbic circuitry, cortical plasticity and the DMN) and note that some therapeutic signal is seen even with limited dosing regimens. Finally, Divito and colleagues urge the conduct of large-scale, blinded, randomised trials to establish efficacy and to clarify mechanisms before psychedelics could be integrated as standard adjunctive treatments for SUD.