ImportanceRenewed interest in the clinical potential of hallucinogens may lead people with depression to a generally more positive view of the use of lysergic acid diethylamide (LSD). Therefore, past-year LSD use among people with depression may be increasing in prevalence.ObjectiveTo assess time trends in the prevalence of past-year nonmedical LSD use by past-year major depression status and the variation in this association by sociodemographic characteristics.Design, Setting, and ParticipantsThis survey study used pooled publicly available data from 478 492 adults aged 18 years or older who were administered the National Survey on Drug Use and Health from 2008 through 2019. Statistical analysis was conducted from December 2022 to June 2023.Main Outcome and MeasuresPast-year major depression diagnoses per criteria from the DSM-IV were analyzed. Logistic regression models examined whether time trends in past-year nonmedical LSD use differed between adults with vs without past-year depression, adjusting for sociodemographic characteristics. Secondary analyses examined whether the trends in LSD use by depression status differed between sociodemographic subgroups.ResultsThe analytic sample included 478 492 adults, of whom 51.8% were female, 56.1% were younger than 50 years, 11.7% were Black, 15.1% were Hispanic, 65.8% were White, and 7.5% were another race. Weighted interview response rates ranged from 64.9% to 75.6% during the study time frame. From 2008 to 2019, past-year use of LSD increased significantly more among adults with major depression (2008 prevalence, 0.5%; 2019 prevalence, 1.8%; prevalence difference [PD], 1.3% [95% CI, 1.0%-1.6%]) compared with adults without major depression (2008 prevalence, 0.2%; 2019 prevalence, 0.8%; PD, 0.6% [95% CI, 0.5%-0.7%]) (difference in difference, 0.8% [95% CI, 0.5%-1.1%]). This difference was particularly pronounced among young adults aged 34 years or younger (PD among those aged 18-25 years with depression, 3.3% [95% CI, 2.5%-4.2%]; PD among those aged 26-34 years with depression, 2.7% [95% CI, 1.6%-3.8%]) and individuals with incomes less than $75 000 per year (PD among those with income <$20 000, 1.9% [95% CI, 1.3%-2.6%]; PD among those with income $20 000-$49 999, 1.5% [95% CI, 1.0%-2.1%]; PD among those with income $50 000-$74 999, 1.3% [95% CI, 0.7%-2.0%]).Conclusions and RelevanceThis study suggests that, from 2008 to 2019, there was a disproportionate increase in the prevalence of past-year LSD use among US adults with past-year depression. Among those with depression, this increase was particularly strong among younger adults and those with lower household incomes. Among individuals with depression who also report LSD use, clinicians should discuss potential strategies for mitigating harm and maximizing benefits in medically unsupervised settings.