Psychedelic for Mental Illness RCT Meta-Analysis and Systematic Review
Abstract
It is estimated that >57 million adults in the United States (>20%) live with a mental illness. The economic burden associated with mental illness is >$5 trillion annually. Extant pharmaceutical and behavioral interventions have demonstrated modest therapeutic efficacy. However, they generally take weeks to reduce symptoms, and in many cases might not provide any acceptable relief. As such, there has been a paradigm shift towards developing rapid-acting interventions. Psychedelics, such as psilocybin, ketamine, and 3,4-methylenedioxymethamphetamine (MDMA), are a burgeoning class of pharmaceuticals receiving scientific and public recognition as a viable rapid-acting intervention program. Off label prescription of psychedelics for various mental health problems has “mushroomed” in the past five years. Though there is no national entity monitoring off-label psychedelic treatment, estimates suggest 500-750 psychedelic specialty clinics currently exist within the United States. Indeed, the size of the United States psychedelic market is estimated to increase to >$10.75 billion by 2027. Given the scope of the mental health crisis, coupled with growing off-label psychedelic prescription movement, it is imperative to understand the efficacy of psychedelic interventions for specific mental illness symptoms. Preliminary research indicates psychedelics might be efficacious in mental illness treatment. For example, ketamine and MDMA have been used to reduce post-traumatic stress disorder (PTSD) symptoms, with small, randomized control trial (RCT) support. Ketamine and psilocybin have similarly been observed as potentially efficacious for treatment-resistant depressive symptoms. Various smaller cohort and case-studies also lend support for psychedelic use for a variety of mental health problems. However, to date, there has been no comprehensive meta-analyses of the entire psychedelic RCT research program. While various studies suggest support for psychedelic use, meta-analysis can demonstrate how much of a therapeutic effect can be expected relative to controls across studies, time points, and outcomes. Extant meta-analyses of psychedelic compounds have been limited to single compounds/symptom profiles. Moreover, most major meta-analyses have only examined single outcome markers, opposed to all possible control comparison time points. Examining all possible outcome markers across time points is important, as significant differences may be evident at one time point, but not another. For example, von Rotz and colleagues recently published an RCT demonstrating highly favorable outcomes for psilocybin relative to passive controls in the treatment of depression. However, their pre-registration (clinicaltrials.gov NCT03715127) indicated they would present results 32 days post-administrations, yet their publication only presented results 14 days post-administration (when results looked favorable to psilocybin). Meta-analysis can be useful for detecting methodological biases (effect size bias in small samples) and important moderating factors that can influence outcomes. Such an approach is important as placebo via expectancy effects has been suggested as a potential action mechanism explaining psychedelic therapeutic efficacy across agents. Indeed, all major psychedelic scholars acknowledge the biological mechanisms behind psychedelic therapeutic effects are unknown. Moreover, psychedelic researchers also have been shown to use psychedelics themselves, signaling a major conflict-of-interest. Additionally, side-effects such as psychoses, worsening of symptoms, and suicidality can accompany psychedelic use, with a recent review indicating that side-effects are often minimalized/under-reported in extant trials. Thus, without knowing why psychedelics provide therapeutic effects raises the question: to what degree do we actually know that psychedelics provide novel therapeutic effects? We seek to address this gap with our proposed meta-analysis. The contribution of the proposed research is significant because it will determine how much better psychedelics are as a class relative to control interventions, which psychedelics are the most incrementally superior and for which symptoms, the degree to which the rapid acting effects of psychedelics are novel, and how long psychedelic therapeutic effects can be expected to last given k administrations. This meta-analysis will help stakeholders, clinicians, and patients determine the degree to which psychedelic therapy is a viable candidate as a rapid-acting evidence-based intervention. Moreover, the proposed meta-analysis aligns with the National Institute of Mental Illness’s mission to transform the understanding and treatment of mental illnesses through basic and clinical research, paving the way for prevention, recovery, and care.
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