New insights into the clinical and nonclinical effects of psychedelic substances: An integrative review.

The authors begin by characterising classic psychedelics as primarily acting at the serotonin 2A receptor (5-HT2A), citing LSD, psilocybin and DMT (commonly used in ayahuasca) as typical examples. Acutely, these substances produce marked alterations of perception, affect and cognition that are strongly shaped by set and setting. Subjective effects include transient increases in positive mood, transcendence of time/space, ineffability, mystical-type experiences (internal and external unity, noetic quality, sacredness) and in high doses ego dissolution. Prevalence estimates indicate substantial lifetime use in the United States—roughly 32 million people (around 9% of the population), with 9.7% of adults aged 16–34 reporting LSD use and 11.8% reporting psilocybin use—whereas European estimates for 15–34-year-olds vary widely (LSD 0.1%–5.4%, psilocybin 0.3%–8.1%). On safety, contemporary analyses described in the review portray classic psychedelics as relatively low in physical harm and addictive potential compared with many recreational drugs. Large US survey analyses report no association, and in some analyses a negative association, between lifetime psychedelic use and markers of psychological distress and suicidality; other analyses report lower rates of certain criminal behaviours among lifetime users. Acute adverse reactions are nonetheless common in controlled settings: for example, one psilocybin administration study found that 31% of participants experienced periods of acute anxiety during sessions, typically transient and not persisting beyond the session. Rare but concerning outcomes reported in case literature include type-2 hallucinogen persisting perception disorder (HPPD), estimated very infrequently (approx. 1/50,000 cases), though prevalence estimates are uncertain and confounded by pre-existing visual symptoms in some reports. The authors also note that people with a genetic predisposition to psychosis are generally advised not to use psychedelics, although empirical evidence for a causal link between psychedelic use and psychosis onset is lacking. Clinical efficacy: multiple early and recent clinical studies suggest antidepressant and anxiolytic effects when psychedelics are administered in controlled, psychotherapeutically supported contexts. For mood disorders, small open-label studies reported large reductions in depressive scores—for example, single-dose ayahuasca studies reported up to 82% reductions in a very small sample, and an open-label psilocybin study found depressive symptom reductions that persisted up to six months in 12 patients with treatment-resistant depression. A placebo-controlled study with 29 patients with treatment-resistant depression reported antidepressant effects after a single ayahuasca dose persisting to seven days. The US Food and Drug Administration has granted psilocybin-assisted therapy “breakthrough therapy” status based on preliminary data. For anxiety related to life‑threatening illness, randomised, double-blind trials with active controls reported significant reductions in existential anxiety and depression-related outcomes: one cross-over study found anxiety reductions in over 80% of participants six months after a single high dose of psilocybin; parallel trials reported sustained increases in life satisfaction at six months. An open-label crossover study administering 200 micrograms of LSD reported reductions in trait anxiety two months after treatment, with no adverse side-effects reported in that sample. Evidence for substance use disorders includes early uncontrolled work and more recent small trials. A smoking cessation study combining psilocybin and cognitive behavioural therapy in 14 participants reported 80% abstinence at six months and 67% abstinence at 30 months, though the lack of a control group limits causal inference. A proof-of-concept alcohol study with 10 participants reported reductions in drinking days and heavy drinking days up to 36 weeks post-treatment. Correlational survey data suggest lifetime psychedelic users were less likely to use opiates in the prior year, but the authors stress that more rigorous controlled studies are needed before firm conclusions can be drawn. Mechanisms: on a neural level, psychedelics are reported to reduce amygdala reactivity and decrease resting-state connectivity within the default mode network (DMN), which has been linked to self-referential processing and rumination in depression. DMN disintegration during ego dissolution has been associated with reduced ruminative thought. Crucially, subjective experiential qualities—particularly mystical-type experiences, feelings of connectedness, perceived insights and emotional breakthroughs—consistently predict therapeutic outcomes across studies, often mediating symptom change, whereas purely sensory/perceptual effects do not. Mediation via increased psychological flexibility is reported in survey-based work. Non-clinical effects: double-blind crossover studies in healthy participants show that psilocybin and LSD reliably induce dose-dependent mystical-type experiences; roughly 60% of participants in some studies rated their experience among the most meaningful of their lives. Reported downstream effects include improvements in subjective wellbeing and quality of life, increased trait openness, enhanced mindfulness and prosocial attitudes. Field data from multi-day mass gatherings indicate that recent psychedelic use—but not use of other substances—predicts self-reported transformative experiences, increased interpersonal connectedness and positive mood; these associations were strongest for very recent use (within 24 hours) and declined with time. Lifetime psychedelic use correlates with greater nature relatedness and self-reported changes in relationship to nature after an experience. Evidence for effects on creativity is currently limited and mostly correlational or based on small uncontrolled samples; some studies report enhanced visual creativity or divergent thinking during or after ayahuasca ceremonies, but rigorous placebo-controlled trials are absent. Duration of effects and synthesis: several clinical trials report effects lasting up to six months, and a first meta-analysis pooling eight clinical studies across psilocybin, LSD and ayahuasca suggests rapid improvements in depressive symptoms lasting up to six months, though the authors of that meta-analysis urge caution because of low data density and limited power. Non-clinical participants frequently rate psychedelic experiences as among their most meaningful even 14 months later, but individual studies report heterogeneous durations—some ayahuasca findings indicate shorter-lived mood benefits. Across the literature, common methodological limitations include small sample sizes, frequent open-label designs, heterogeneous requirements regarding concurrent antidepressant medication, self-selected samples and a lack of long-term follow-up, all of which constrain causal inference and generalisability.

Forstmann and Sagioglou interpret the assembled evidence as broadly promising: psychedelics, when administered in controlled, supportive contexts and often combined with psychotherapy, show potential for rapid and sometimes sustained reductions in depressive and anxiety symptoms, and preliminary signals for benefit in substance use disorders. They place these findings in continuity with earlier research while emphasising the renewed methodological rigour of contemporary studies. The authors highlight that subjective, mystical-type experiences and related phenomena such as connectedness and perceived insights appear central to therapeutic benefit, and that neural changes such as DMN disintegration and reduced amygdala reactivity may help explain these effects. The review also underscores substantial uncertainties and methodological limits. Many trials remain small, several are open-label, long-term follow-ups are sparse and self-selection biases are frequent. Heterogeneity across studies—for example in whether patients discontinued antidepressant medication—complicates synthesis. Safety signals are largely reassuring at the population level, but acute adverse reactions occur commonly in controlled settings and rare conditions such as HPPD are reported in case literature with uncertain prevalence. The authors therefore caution against over-interpretation and call for larger, rigorously controlled, and longer-term studies that clarify causal mechanisms, boundary conditions and risk factors for adverse outcomes. Looking ahead, the authors recommend developing clearer operational criteria and measurement tools for mystical-type experiences, investigating which person- and environment-level factors promote therapeutic experiences, and conducting more comprehensive meta-analyses as the evidence base grows. They further note policy implications: contemporary findings raise questions about whether current legal restrictions remain appropriate given scientific and clinical developments, and whether regulatory re-evaluation could remove barriers to research while preserving safety safeguards.