Association Between Lifetime Hallucinogen Use and Valvular Heart Disease: Findings from the All of Us Research Program

Yang and colleagues note that interest in hallucinogens such as psilocybin, LSD and MDMA has increased because of their growing clinical and recreational use, alongside more permissive policy trends and reduced perceived risk. At the same time, there are unresolved safety questions, including reports of acute cardiovascular effects and a theoretical concern that some hallucinogens might contribute to valvular heart disease (VHD) through prolonged activation of the serotonin 5-HT2B receptor, a mechanism previously implicated in drug-induced valvular fibrosis. The authors emphasise that epidemiological evidence on this possible association is scarce. The study set out to use the All of Us Research Program to explore whether lifetime hallucinogen use was associated with VHD in US adults with linked electronic health record data. The authors present the analysis as exploratory and hypothesis-generating, stating that the cross-sectional design and the single-item lifetime exposure measure limit causal interpretation. They also frame the work as responding to recent FDA guidance encouraging evaluation of potential psychedelic-related VHD.

This was a cross-sectional observational analysis using version 7 of the NIH All of Us Research Program dataset. The researchers included adults aged 18 years or older who had completed the Lifestyle survey. From 413,457 enrolled participants, they excluded those who had not completed that survey, then removed people with congenital heart disease, rheumatic heart disease or Marfan syndrome to reduce pre-existing condition bias, and finally excluded those with missing sociodemographic data. The final analytic sample was 286,842 participants. Lifetime hallucinogen use was self-reported in the Lifestyle survey via a question asking which substances participants had ever used in their lifetime, with hallucinogens described as including LSD, mushrooms, PCP, Special K and ecstasy. The paper grouped several substances under this exposure category, including LSD, psilocybin/mushrooms, MDMA/ecstasy, ketamine and phencyclidine (PCP). VHD was identified from electronic health records using relevant SNOMED diagnostic codes. The study also assessed lifetime smoking, lifetime cannabis use and other illicit substance use, and extracted a range of health conditions from EHRs, including hypertension, hyperlipidaemia, diabetes, coronary arteriosclerosis, obesity, heart failure, lupus and arrhythmia, as well as sociodemographic characteristics from the Basics survey. The researchers first compared participant characteristics by hallucinogen-use status using t-tests and chi-squared tests. They then fitted multivariable logistic regression models to estimate adjusted odds ratios for the association between lifetime hallucinogen use and VHD. Model selection was performed with a bidirectional stepwise approach based on Akaike Information Criterion (AIC); lifetime cannabis use and other illicit substance use were removed from the final model. Collinearity was assessed with adjusted Generalised Standard Error Inflation Factors, and all values were below 1.4. Analyses were performed in R within the All of Us Workbench environment, and statistical significance was set at p<0.05.

The final sample had a mean age of 50.8 years and was 61.4% female, 60.6% White, 53.0% married, 50.2% unemployed and 93.9% insured. About 13.2% reported lifetime hallucinogen use. Compared with non-users, hallucinogen users were younger and more likely to be male, White, non-Hispanic, divorced or never married, employed, and to have at least some college education. They also reported higher rates of smoking, lifetime cannabis use and other illicit substance use, all with p<0.001. In unadjusted analyses, lifetime hallucinogen use was associated with lower odds of VHD, with VHD prevalence of 3.6% among users versus 4.7% among non-users and an odds ratio of 0.76 (95% CI 0.72-0.81; p<0.001). After adjustment, the association reversed direction: lifetime hallucinogen use was associated with modestly higher odds of VHD, with an adjusted odds ratio of 1.08 (95% CI 1.01-1.55; p=0.017). The paper notes that this association was similar in the full model and the AIC-selected final model. The adjusted model also found increased odds of VHD with older age, female sex, other sex category, never-married status, higher income categories and college education. Several health conditions were strongly associated with VHD, including arrhythmia (aOR 3.42), heart failure (aOR 2.74), hyperlipidaemia (aOR 2.34), hypertension (aOR 2.28), coronary arteriosclerosis (aOR 2.00) and lupus (aOR 1.91). Lower odds were reported for lower-income categories, non-Hispanic Black race, uninsured status, lifetime smoking of at least 100 cigarettes, and diabetes diagnosis.

The authors interpret their findings as showing a small but statistically significant association between self-reported lifetime hallucinogen use and EHR-derived VHD after adjustment for sociodemographic factors and health conditions. They describe the study as the first epidemiological analysis of this question and argue that the result is noteworthy given increasing recreational use of hallucinogens and the changing legal and clinical environment. However, they repeatedly stress that the analysis is exploratory and hypothesis-generating rather than confirmatory. They place the finding in the context of earlier theoretical and pharmacological work linking serotonergic drugs to VHD through 5-HT2B receptor activation and valvular fibrosis. The authors also note that the direction of the association changed from apparently protective in the crude analysis to positive after adjustment, which they attribute to confounding because hallucinogen users in the sample were younger and had fewer cardiovascular risk factors. They suggest that this pattern underscores the complexity of the relationship and the need for more robust longitudinal research with better exposure measurement. They also mention that different hallucinogens may differ in 5-HT2B affinity and broader receptor pharmacology, so substance-specific effects may vary. The authors acknowledge several limitations. The cross-sectional design prevents causal inference and does not establish temporality. Lifetime use was self-reported and did not capture frequency, recency or specific substance use in detail, and the broad hallucinogen category may have mixed drugs with different cardiovascular mechanisms, including ketamine and PCP, which are not thought to act through 5-HT2B. They also note potential recall, social desirability and selection bias, residual confounding, and limited representativeness because All of Us uses convenience sampling and oversamples some under-represented groups. They call for prospective longitudinal studies, incorporation of echocardiographic data, and further pharmacological work. In terms of implications, they suggest clinicians and policymakers should be aware of a possible cardiovascular signal and consider monitoring or screening on a case-by-case basis, particularly in frequent users or people engaging in long-term microdosing.

The authors conclude that, despite important limitations, the study detected a potential signal linking hallucinogen use with VHD and that this warrants further, more rigorous clinical research. They emphasise that the findings should not be treated as confirmatory and instead should guide future hypothesis testing. They also state that ongoing research into the cardiovascular effects of hallucinogens is important for individuals, clinicians and policymakers as both recreational and therapeutic use continues to expand.