Psilocybin Therapy for Methamphetamine Use Disorder and HIV - PROJECT SUMMARY / ABSTRACT Methamphetamine use disorder (MeUD) is a growing public health crisis that disproportionately affects people with HIV (PWH). Beyond its direct neuropsychiatric and cardiovascular harms, methamphetamine use among PWH contributes to antiretroviral therapy non-adherence and HIV viremia, driving both disease progression and transmission. Despite the severity of this syndemic, there are no FDA-approved treatments for MeUD, and existing interventions remain limited in accessibility, effectiveness, and scope. These challenges further restrict the adoption and benefits of innovative HIV pharmacotherapies among people with MeUD, underscoring an urgent need for novel therapeutic strategies. Emerging evidence suggests that psilocybin, a serotonergic psychedelic and 5-HT2A-receptor agonist, may have anti-addictive effects when combined with structured psychological support. Early phase studies have shown substantial reductions in alcohol, tobacco, and cocaine use, likely through psilocybin-induced modulation of brain networks involved in impulsivity, cognitive rigidity, and negative self-appraisal—neurobehavioral patterns that also underlie MeUD and HIV care disengagement. This proposal aims to conduct the first placebo-controlled trial of psilocybin therapy for MeUD, and the first outpatient psilocybin therapy trial for MeUD in the U.S., through a double-blind, randomized pilot study focused on PWH with moderate-to-severe MeUD (N=30). Participants will be randomized 1:1 to receive either 25 mg (moderate-high dose) or 1 mg (very low dose) oral psilocybin, each embedded within a 6-week, manualized motivational enhancement therapy (MET) framework. Primary outcomes will focus on feasibility (based on pre- defined benchmarks), acceptability, and safety, including qualitative analysis of post-intervention semi- structured interviews with participants. Exploratory outcomes will include changes in methamphetamine use, HIV-related indicators, and candidate neuropsychological mechanisms, measured through a combination of self-report and biomarkers, to inform future hypothesis-driven research. Following a double-blinded phase, all participants will be offered an optional open-label 25 mg psilocybin dose with additional preparatory and integration support—designed to enable exploratory within-subject comparisons and to improve retention, reduce nocebo-related distress, and inform whether future trials should include one or two psilocybin dosing sessions. The study will be conducted at UCSF using an innovative, community-engaged model that integrates existing, university-based Schedule I drug research infrastructure with recruitment from safety-net programs across San Francisco. Eligibility criteria reflect the real-world complexities of MeUD patients, including those with co-occurring substance use and histories of stimulant-induced psychosis. This early-phase study will fill a critical gap by evaluating psilocybin’s potential to mitigate the syndemic of MeUD and HIV while building institutional capacity for public health-focused Schedule I drug research and generating preliminary data to inform the development of larger efficacy trials.
