Classic psychedelic use is associated with reduced psychological distress and suicidality in the United States adult population

Hendricks and colleagues situate their study within a context of persistently high rates of mental illness and suicide worldwide and a recognised need for novel interventions targeting suicidality. Classic psychedelics (notably DMT, LSD, mescaline, and psilocybin) are described as serotonergic 5-HT2A agonists with a long history of sacramental and therapeutic use and a recent resurgence of clinical research suggesting potential benefits for mood, anxiety, and substance misuse. The authors outline neurobiological and psychological mechanisms by which psychedelics might reduce suicide risk, including modulation of 5-HT2A receptors, promotion of neuroplasticity, normalisation of default mode network activity, increases in personality openness and spirituality, and capacity to aid processing of traumatic memories. The paper sets out to test whether lifetime use of classic psychedelics is associated with reduced psychological distress and suicidality at the population level. Using pooled data from five years of the US National Survey on Drug Use and Health (NSDUH; 2008–2012), the investigators hypothesised that lifetime classic psychedelic use would be linked to lower odds of past month psychological distress and lower odds of past year suicidal thinking, planning, and attempts. They argue that, given regulatory barriers to experimental research, large-scale survey data provide a pragmatic avenue to examine these associations in real-world settings.

The study used cross-sectional data pooled from adult respondents (>18 years) to the NSDUH collected between 2008 and 2012. The NSDUH employs a complex probability sampling design to estimate substance use and mental illness prevalence in the non-institutionalised US civilian population; interview response rates were approximately 75%. Interviewers administered standardised questions in participants' homes using prerecorded items and computer-assisted responses. The investigators created unique respondent identifiers across years using the Cantor pairing function and restricted analyses to those with valid data on lifetime classic psychedelic use and all covariates. Lifetime classic psychedelic use (primary independent variable) was coded positive for respondents who reported ever using DMT, ayahuasca, LSD, mescaline, peyote/San Pedro, or psilocybin. A separate NSDUH item that combined DMT with other compounds (AMT, 5-MeO-DIPT) was considered but ultimately not used to define classic psychedelic exposure because it did not permit disaggregation of DMT and included substances with ambiguous classification; a post-hoc check showed including that item added only 362 individuals and did not alter results. Primary outcomes were past month psychological distress measured by the Kessler K6 scale, and past year suicidal thinking, suicidal planning, and suicide attempt (binary items). Multivariate logistic regression (PROC SURVEYLOGISTIC in SAS 9.3) with NSDUH sampling weights and design variables was used to estimate associations between lifetime classic psychedelic use and each outcome. Models adjusted for a comprehensive set of covariates: age category, gender, ethnoracial identity, educational attainment, annual household income, marital status, self-reported engagement in risky behaviour, and lifetime illicit use of a range of other substances (cocaine, other stimulants, sedatives, tranquilizers, heroin, pain relievers, marijuana, MDMA/ecstasy, PCP, and inhalants). The complex survey design and sampling weights were accounted for in all analyses.

The analytic sample comprised 191,382 respondents, of whom 27,235 reported lifetime classic psychedelic use (13.6% weighted). Substance-specific lifetime counts included 391 reporting DMT (0.1% weighted), 26 reporting ayahuasca (0.008% weighted), 18,152 reporting LSD (10.2% weighted), 4,687 reporting mescaline (3.5% weighted), 3,540 reporting peyote or San Pedro (2.4% weighted), and 20,274 reporting psilocybin (8.9% weighted); these categories overlap because respondents could report use of more than one substance. Outcome prevalences were: past month psychological distress 12,657 respondents (4.8% weighted), past year suicidal thinking 10,445 (3.8% weighted), past year suicidal planning 3,157 (1.1% weighted), and past year suicide attempt 1,716 (0.5% weighted). Lifetime classic psychedelic use was more common among people aged 26–64 and uncommon among those 65 and older. It was also concentrated among men, non-Hispanic Whites and Native Americans/Alaska Natives, those with higher educational attainment and income, divorced/separated or never-married individuals, those reporting greater engagement in risky behaviour, and people with lifetime illicit use of other substances. Only 240 lifetime classic psychedelic users (0.9% weighted) reported never having used any other illicit drug, whereas 85,601 respondents among non-users (58.2% weighted) reported never using other illicit drugs. In adjusted multivariate models, lifetime classic psychedelic use was associated with reduced odds of each primary outcome: past month psychological distress (weighted OR = 0.81, 95% CI 0.72–0.91, p = 0.0002), past year suicidal thinking (weighted OR = 0.86, 95% CI 0.78–0.94, p = 0.001), past year suicidal planning (weighted OR = 0.71, 95% CI 0.54–0.94, p = 0.01), and past year suicide attempt (weighted OR = 0.64, 95% CI 0.46–0.89, p = 0.008). By contrast, lifetime illicit use of most other drug categories was either unrelated or associated with increased odds of psychological distress and suicidality; reported ORs for those substances were generally above 1.0, with a few exceptions noted (e.g. PCP and past month psychological distress; MDMA/ecstasy and several suicidality outcomes showed no significant associations).

Hendricks and colleagues interpret the findings as consistent with their hypothesis that lifetime classic psychedelic use is associated with lower psychological distress and suicidality at the population level. They quantify these associations as a 19% lower likelihood of past month psychological distress, 14% lower likelihood of past year suicidal thinking, 29% lower likelihood of past year suicidal planning, and 36% lower likelihood of past year suicide attempt among lifetime classic psychedelic users, after adjustment for numerous demographic and substance-use covariates. The authors note that these population-level associations align with experimental and clinical studies pointing to antidepressant, antiaddictive, prosocial, and neurobiological effects of classic psychedelics that could plausibly reduce suicide risk. The investigators acknowledge several important limitations. Chief among these is the cross-sectional, self-report nature of the data, which precludes causal inference and may be subject to reporting biases. The available NSDUH variables also constrained the depth of analysis; for example, the dataset does not permit examination of dose–response relationships, context of use, or temporal ordering of psychedelic use relative to mental health outcomes. Residual confounding is possible: premorbid personality traits or spiritual values that predispose someone to use psychedelics might also protect against suicidality, and these factors could contribute to the observed associations. The authors also concede that some psychedelic users may possess premorbid liabilities for suicidality given their higher rates of risky behaviour and other illicit drug use. Potential individual-level harms are considered: psychedelics can exacerbate psychotic disorders, pose dangers in hazardous environments, and sometimes provoke acute anxiety or paranoia. Nevertheless, the authors highlight that the apparent protective association emerged despite the uncontrolled, naturalistic contexts in which most use occurred, suggesting that clinical administration under controlled conditions might further potentiate benefits. Finally, regulatory barriers (Schedule I status) and limited funding are cited as major obstacles to the clinical research the authors deem necessary. They recommend longitudinal and clinical studies to test efficacy for suicidality and related pathologies, and to investigate mediators and mechanisms of psychedelic effects to optimise therapeutic application.

The authors conclude that, despite regulatory and historical controversies, accumulating evidence including their population-level analysis suggests classic psychedelics may have potential to reduce suffering associated with mental illness and suicidality. They call for further rigorous research to characterise safety, efficacy, mechanisms, and clinical applications, with the ultimate aim of harnessing any therapeutic capacity these substances may possess.