Age moderates the relationship between psychedelics use and mental health in naturalistic settings

The paper situates its inquiry in the context of the persistent global burden of depression and anxiety across adulthood and growing interest in psychedelics as potential interventions. The authors distinguish between "classic psychedelics" (primarily 5-HT2A agonists such as psilocybin, LSD and DMT) and "non-classic psychedelics" (e.g., ketamine, MDMA, ibogaine) that differ in neuropharmacology despite some experiential overlap. They note that clinical research has promising but limited evidence, often based on small or narrowly selected samples, while naturalistic (recreational) use is increasing and produces mixed findings for mental health outcomes. Age emerges as a plausible moderator because younger people reportedly experience more intense mystical or ego-dissolution phenomena and may be more vulnerable to acute adverse effects, while ageing is associated with reduced 5-HT2A receptor density and other neurobiological changes that could alter psychedelic responsiveness. Di Gregorio and colleagues therefore set out to test two primary questions in a cross-sectional, naturalistic sample: (1) whether lifetime use of classic and non-classic psychedelics is associated with differences in anxiety, depression, wellbeing, and life satisfaction compared with non-users; and (2) whether these associations vary across the adult lifespan. To address gaps created by exclusion of older adults in clinical trials and the predominance of younger participants in observational studies, the study deliberately recruited an age-diverse sample and classified participants into mutually exclusive groups (Classic-only, Non-classic-only, Classic+ [mixed use], and non-users) to enable theoretically informed comparisons while accounting for polydrug patterns.

The researchers conducted an anonymous, cross-sectional international survey delivered via Qualtrics. Inclusion criteria were being at least 18 years old and fluent in English. Recruitment occurred between November 2024 and August 2025 through multiple channels (Prolific, a university participant pool, social media, email, snowball sampling and other online platforms) to capture a broad, age-diverse and ecologically valid sample. The extracted text reports that 1,270 individuals enrolled and 182 did not complete the survey, yielding a final sample of 1,088; elsewhere the extraction refers to 1,008 adults as the full sample, and the text does not resolve this discrepancy. Participants supplied demographics and detailed lifetime psychedelic use information (which substances, age at first use, frequency within life-stage bands, typical dose category, motives, presence/absence of a guide, concurrent substance use and whether they had ever had a mystical experience). A checklist adapted from the MEQ-30 assessed ten mystical-type items (e.g., unity, transcendence of time/space, ego dissolution, encounters with the divine, feelings of love/compassion). Mental health measures were standard self-report scales: GAD-7 for anxiety (0–21), PHQ-9 for depression (0–27), WHO-5 for wellbeing (converted to 0–100), and the Satisfaction With Life Scale (SWLS; 5–35). Internal consistency was high (Cronbach's α: GAD-7 = .92; PHQ-9 = .89; WHO-5 = .90; SWLS = .91). If a participant had one missing item on a scale it was imputed by their mean on the remaining items; participants with two or more missing items were excluded from that scale's analyses. Substances were classified pharmacologically: classic psychedelics were defined as primary 5-HT2A agonists (e.g., psilocybin, LSD, DMT, mescaline, ayahuasca, 4-AcO-DMT), while non-classic psychedelics included dissociatives (ketamine, PCP, MXE, DXM/DXO, nitrous oxide), entactogens (MDMA, MDA, 6-APB) and oneirogenics (ibogaine). Atypical serotonergic compounds reported in free text (e.g., DOx, 2C-x, NBOMe, 5-MeO) were not classed as classic for analysis. For primary comparisons participants were grouped into three mutually exclusive categories: Non-Classic Only, Classic Only, and Classic+ (classic plus non-classic/atypical serotonergic substances). Lifetime cumulative use was estimated by converting frequency categories within six age bands into numeric midpoints and summing; years since last use were estimated by subtracting a midpoint for the most recent age-band of use from current age. For analysis the researchers fitted structural equation models (SEMs) with latent variables for anxiety, depression, wellbeing and life satisfaction. Each latent outcome was regressed on orthogonal contrast codes representing psychedelic-use category, age, and their interaction. Orthogonal contrasts allowed targeted hypothesis testing while keeping contrasts statistically independent. Models used robust standard errors with a Satorra–Bentler correction (MLM in Lavaan), and gender was included as a covariate to account for group imbalances. Follow-up analyses restricted to users examined additional use-history variables (cumulative lifetime use, age at first use, typical dose, recency). Significant interactions were probed with simple-slopes at mean ± 1 SD of age and, when near significance, with Floodlight (Johnson–Neyman) procedures. Logistic regression models assessed whether age and psychedelic-use contrasts predicted likelihood of reporting a mystical experience.

Participant grouping and use characteristics: The extracted text reports that, across the analysed sample, 562 participants reported no lifetime psychedelic use, 90 reported exclusive non-classic use (Non-classic-only), 126 reported exclusive classic use (Classic-only), and 310 reported mixed use (Classic+). Most psychedelic users initiated use between ages 18 and 25. Recreational motives dominated (reported by 77–93% across groups), therapeutic motives were reported by 6–20%, reported dosages were broadly similar across groups, and 83–86% of users reported taking psychedelics without a guide. Lifetime mystical experiences were reported by 60% of Classic-only users, 73% of Classic+ users, and 35% of Non-classic-only users. Primary SEM findings — anxiety and depression: In full-sample SEMs age was negatively associated with anxiety (β = -0.151, p < 0.001) and depression (β = -0.222, p < 0.001). There was a main effect in the anxiety model indicating lower anxiety among classic-psychedelic users (Classic-only and Classic+) compared with Non-users and Non-classic-only users (β = 0.093, p = 0.014, as reported). Crucially, a significant Age × Classic-vs-Nonclassic/Non-user interaction emerged for anxiety (β = -0.147, p < 0.001). Simple-slopes probing this interaction showed that classic-psychedelic use was associated with lower anxiety in younger adults (approximately 23 years: β = 0.227, p < 0.001), the association attenuated at the sample mean age (≈36 years: β = 0.083, p = 0.023), and was absent in older adults (≈50 years: β = -0.06, p = 0.201). For depression there was no clear main effect of psychedelic-use category (the Classic vs Non-classic/Non-user contrast approached significance: β = 0.073, p = 0.052), but there was a significant Age × Classic contrast interaction (β = -0.089, p = 0.017). Simple-slopes indicated lower depressive symptoms among classic users only in younger adults (β = 0.148, p = 0.009), with no significant associations at mean or older ages. Wellbeing and life satisfaction: WHO-5 wellbeing scores showed no significant main effects or age interactions with psychedelic-use category. Life satisfaction (SWLS) produced a different pattern: Non-classic-only users reported higher life satisfaction than Non-users (β = -0.084, p = 0.019). Life satisfaction also showed an Age × Classic contrast interaction (β = 0.087, p = 0.039). Simple-slopes suggested no differences at younger or average ages, but a trend toward lower life satisfaction for Classic-only/Classic+ users in older participants (β = 0.114, p = 0.057). A Johnson–Neyman analysis identified a significant lower life satisfaction for Classic users versus Non-classic/non-users at age 53 (p = 0.047). Robustness to use-pattern controls: Analyses restricted to psychedelic users (n = 562, per extracted text) replicated the age-moderated association between classic use and anxiety/depression for the Classic-only/Classic+ vs Non-classic-only contrast. In user-only simple slopes younger Classic users had lower anxiety than Non-classic-only users (β = 0.158, p = 0.017), whereas older classic users showed higher anxiety than non-classic users (β = -0.116, p = 0.038). Depression showed a similar trend though within-age-group comparisons did not reach significance. Importantly, controlling for years since last use, typical dose, and cumulative lifetime use did not eliminate the Age × Classic-use interactions: for anxiety the interaction remained significant when adjusting for years since last use (β = -0.138, p = 0.002), dose (β = -0.148, p = 0.001), and cumulative use (β = -0.144, p = 0.001). For depression similar interaction coefficients remained significant (years since last use β = -0.097, p = 0.024; dose β = -0.105, p = 0.025; cumulative β = -0.096, p = 0.031). The authors therefore report that recency, dosage and cumulative exposure do not account for the age-dependent associations observed. Mystical experience analyses: Logistic regression showed that participants who had used classic psychedelics (Classic-only and Classic+ combined) were more likely to report mystical experiences than non-classic-only users (OR = 1.560, p < 0.001). Higher reported dose was associated with increased odds of mystical experience (OR = 1.70, p < 0.001). The authors report that Classic+ users were more likely than Classic-only users to report mystical experiences (reported OR = 0.746, p = 0.009, noting this is how it appears in the extracted text). Significant interactions with age were observed (Age × Classic contrast: OR = 0.984, p = 0.024; Age × Classic+ vs Classic-only: OR = 1.973, p = 0.002). Simple-slopes indicated that classic users at younger and mean ages were significantly more likely to report mystical experiences than non-classic-only users, but this effect was not significant at older ages. When mystical experience was introduced into the mental-health models it attenuated the age-dependent association between classic use and depression (Age × Classic contrast became non-significant: β = -0.084, p = 0.064), whereas the age-dependent association with anxiety remained significant (β = -0.124, p = 0.006). The authors therefore report that age-related differences in mystical experience explain the age-dependent association between classic-psychedelic use and depression but not the equivalent pattern for anxiety.

Di Gregorio and colleagues interpret their results as identifying chronological age as a central moderator of the relationship between lifetime psychedelic use and mental-health measures in naturalistic settings. They emphasise that classic psychedelic use was associated with lower anxiety and depression only among younger adults in their sample; in later adulthood the pattern for anxiety reversed, with non-classic psychedelics associated with more favourable anxiety outcomes than classic compounds. Life satisfaction followed a related, age-dependent pattern: classic use was linked to higher levels among younger participants but to lower life satisfaction among older users (with a Johnson–Neyman cutoff observed at about 53 years). These age-dependent patterns were not explained by recency of use, cumulative lifetime exposure, dose, or age at first use, according to their adjusted models, suggesting that chronological age itself is the key moderator identified in this dataset. The authors propose converging biological, neural and psychological mechanisms that could underlie the observed age moderation. At a molecular level they point to age-related declines in 5-HT2A receptor density that could reduce the intensity of classic-psychedelic experiences. At the neural and cognitive levels they cite reduced plasticity and cognitive flexibility and greater stability/segregation of brain networks with age, which may limit reorganisation following salient experiences. Psychologically, more mature ego structures in older adults may make them less susceptible to ego-dissolution states. Together, these factors are presented as plausible contributors to attenuated psychedelic responsiveness with age. The distinction between classic and non-classic psychedelics was important to the authors' interpretation. They argue that including a Non-classic-only group allowed a stricter control for openness to altered states and revealed potentially clinically relevant differences: non-classic compounds may retain or show greater effectiveness for anxiety in older adults because their primary molecular targets decline less with age than 5-HT2A, and they may pose different medical risk profiles in older populations. The authors also note that Classic+ users were more likely to report mystical experiences in older age than Classic-only users, suggesting that co-use patterns could shape subjective experience and potentially outcomes, though they cannot disentangle pharmacological from baseline trait differences in this study. Regarding mechanisms linking experience to outcomes, the authors report that mystical-type experiences appear more important for depression than for anxiety: controlling for mystical experience removed the age-dependent association between classic use and depression but not the age-dependent association for anxiety, implying symptom-specific psychological mediators. The authors also note domain-specific findings: psychedelics did not affect general wellbeing (WHO-5) in this sample, perhaps due to ceiling effects or the scale's limitations, while non-classic use correlated with higher life satisfaction, which may relate to contextual or social factors associated with use. The authors explicitly acknowledge methodological limitations: the study's cross-sectional design precludes causal inferences and is vulnerable to selection and self-selection biases (pre-existing psychological traits may differ between user groups). All outcomes were self-reported and socioeconomic confounders were not accounted for. They note that use of a Non-classic-only comparison group partially mitigates selection bias by including people with similar openness to altered states. Finally, they highlight strengths: a relatively large, age-diverse sample and analyses that model latent variables and orthogonal contrasts to test theoretically motivated hypotheses, as well as ecological validity from capturing real-world polydrug patterns. The authors argue these results motivate future longitudinal and clinical studies that explicitly test age as a moderator of psychedelic treatment effects and examine compound-specific and context-specific mechanisms.