Wellcome Leap Psilocybin for OUD

The Opioid Crisis: Currently in its third wave, the opioid epidemic involves the prevalence of lethal levels of fentanyl in drugs, leading to a surge in opioid-related deaths. Reports indicate a record-breaking number of over 107,000 drug-related overdose deaths in 2021-2022, with opioids contributing to more than 75% of these fatalities. Beyond fatal overdoses, nearly 1 million non-fatal overdoses occurred in 2017, carrying significant, long-lasting consequences. Those who experience non-fatal overdoses are more prone to subsequent overdoses and have a higher likelihood of death within a year, primarily due to drug-related issues. The escalating cases of opioid use disorder (OUD) emphasize the critical need for innovative treatments to address the associated challenges, including neurocognitive difficulties and poor clinical outcomes. While medication-assisted treatment (MAT) like methadone or buprenorphine effectively alleviates withdrawal symptoms and reduces overdose risk, illicit drug use persists, and non-adherence to MAT remains a challenge. The opioid overdose crisis demands urgent attention and necessitates the development of treatments capable of making a significant impact.

Psilocybin: In response to the need for improved treatments, there's a growing interest in psychedelic-assisted treatment (PAT), particularly involving psilocybin (PSI). Clinical trials support the use of PAT in controlled medical contexts, with 105 trials registered in the past 20 years covering various mental health and other conditions. PSI (at single doses in the proposed range) has shown preliminary promise for depression, alcohol use disorder, and tobacco-use disorder. However, its potential benefits for OUD remain unknown. This proposal aims to determine whether PSI enhances critical OUD clinical outcomes, such as relapse, overdose, and MAT adherence. Importantly, the investigators will test how PSI produces its benefits through its impact on brain and bio-behavioral targets, thus linking potential biomarkers to clinical outcomes.

Cognitive Flexibility: The ability to change thoughts, emotions, and behaviors in response to changes in circumstance (to "flex") has strong survival value. When the brain cannot "flex", one can experience a range of mishaps, from small (turning left rather than right 'out of habit') to much larger ones. Being 'stuck' is a problem that appears in many disorders. For example, individuals with depression may get 'stuck' in dark ruminating thoughts; individuals with OCD may get 'stuck' in repetitive thoughts and behaviors; people with substance use disorders get 'stuck' over-responding to drug reward signals and pursue the drug despite negative consequences. Recent research shows that PSI facilitates intermediate and long-term improvements in cognitive flexibility, raising the hope that it can 're-set' the brain and enable new thoughts, emotions, and behaviors. Cognitive flexibility is often measured by tasks that quantify how successfully one can shift between changing mental rules to complete a task. Using such tasks, there is evidence of cognitive flexibility deficits in people with OUD, but research has not specifically examined the impact of improved cognitive flexibility on OUD clinical outcomes. To date, one study showed that neurocognitive training in executive function (EF), including cognitive flexibility, is associated with reduced opioid use, while a non-OUD study found that higher baseline cognitive flexibility was related to better substance use treatment retention. This proposal will be the first to test whether putative PSI-related improvements in cognitive flexibility will lead to more favorable OUD clinical outcomes.

Other Executive Functions: Importantly, cognitive flexibility is a complex capability that depends on the integrated action of several other basic executive functions (EFs): attention, working memory, and inhibition of thoughts, feelings, or actions. Further, each of these basic EFs, together with cognitive flexibility, are needed for effective and efficient planning and decision-making. Individuals who use drugs demonstrate impairment in a variety of these fundamental EFs. In OUD populations, deficits are evident across most EF domains, including working memory, attention, inhibition, and decision-making, which may relate to or underly their cognitive inflexibility. Studies have found that performance on EF tasks (and the neural underpinnings of EF in the prefrontal cortex [PFC]) indeed correlate with clinical outcomes such as treatment non-adherence (e.g., working memory) and drug use/relapse (e.g., poor inhibition) in substance-use disorders generally, and with reduced abstinence in OUD. Whether these multiple EF deficits predate, or even predispose, drug use - they are likely compounded by drug exposure, including non-fatal opioid overdoses that produce hypoxic-related brain injuries, leading to further neurocognitive deficits. In sum, there is good preliminary evidence for deficits in the several component EFs underlying cognitive flexibility in OUD. By measuring these separately, the current proposal will be able to determine which of these targets are most impacted by PSI, and their relative importance for outcome prediction.

What's "special" about psilocybin? PSI has likely been in use by humans for millennia, originally as a religious or spiritual agent due to its dramatic subjective effects, including hallucinations and mystical experiences. However, scientists have more recently understood that some of the effects - such as increased sense of connectedness, openness, and change in perspective - can produce long-lasting change and improved mental health. Indeed, psychometric instruments capturing non-ordinary states of consciousness and psychological constructs have reliably predicted clinical treatment outcomes, including substance use disorder outcomes. Some theorists have proposed that these dramatic drug effects may reflect a profound initial 'loosening' of top-down control over limbic and sensory regions, resulting in improved flexibility and adaptive behavior. Though the current proposal will not be able to test all features of this hypothesis, the investigators will capture the special acute phenomenology of the drug state and test for the fundamental feature of flexibility. Further, the investigators will determine the relative role of the basic EF components of flexibility and test the importance of all these factors (alone and in combination) for obtaining clinical benefit from the drug. This study will provide a critical foundation for understanding the potential of 5HT2A agonists in OUD, with treatment implications for several other disorders where cognitive inflexibility, 'getting stuck', is a core feature.