Psilocybin-assisted therapy for major depressive disorder: An exploratory placebo-controlled, fixed-order trial

Abstract

Background: Several early phase studies have demonstrated that psilocybin-assisted therapy has rapid-acting and persisting antidepressant effects from just one or two doses. However, methodological limitations (e.g., placebo-control, blinding) limit interpretability of the existing literature. Methods: In an exploratory placebo-controlled, within-subject, fixed-order study, individuals with moderate to severe major depressive disorder were administered placebo ( n = 19) followed by psilocybin (0.3 mg/kg) ( n = 15) 4 weeks later. Dosing sessions were embedded within an manualized course of psychotherapy. Enhanced blinding procedures were used. Depression, anxiety, and quality of life were measured over a 16-week study period. Results: Depression and anxiety significantly improved following both placebo and psilocybin with no significant difference in the degree of change between the two conditions. However, antidepressant effect sizes were larger after psilocybin ( d′ = 1.02–2.27) than after placebo ( d′ = 0.65–0.99) and there were high rates of response (66.7%) and remission (46.7%) following psilocybin administration. Antidepressant effects following psilocybin persisted, on average, for 2 months and there were persisting improvements in mood-related quality of life domains. The strength of mystical-type experience during psilocybin dosing was not correlated with subsequent antidepressant effects. Conclusions: The results of this exploratory study highlight the complex interplay between expectancy, therapy effects, and drug/placebo effects in psychedelic-assisted psychotherapy studies. Nonetheless, the acute and persisting clinical improvements observed following psilocybin support further study of its potential in the treatment of major depression. Future studies should more explicitly mitigate and measure expectancy effects and assess the impact of repeated dosing and different forms of psychotherapeutic support.

Older adults in psychedelic-assisted therapy trials: A systematic review

“…Through the review of their references, 20 additional articles were identified. After excluding ineligible articles and secondary analysis, 36 articles were identified for inclusion in this systematic review (Anderson et al, 2020; Bogenschutz et al, 2015, 2022; Bouso et al, 2008; Carhart-Harris et al, 2016, 2021; Danforth et al, 2018; Davis et al, 2021; Gasser et al, 2014; Goodwin et al, 2022; Griffiths et al, 2016; Grob et al, 2011; Grof et al, 1973, 1972; Holze et al, 2022; Johnson et al, 2014; Kast, 1967; Kurland et al, 1971; Mccabe et al, 1972; Mitchell et al, 2021; Mithoefer et al, 2011, 2018; Monson et al, 2020; Moreno et al, 2006; Oehen et al, 2013; Osorio et al, 2015; Ot’alora et al, 2018; Pahnke et al, 1969; Palhano-Fontes et al, 2019; Richards et al, 1977; Ross et al, 2016; Sanches et al, 2016; Savage and McCabe, 1973; Schneier et al, 2023; Sloshower et al, 2023; Wolfson et al, 2020). A PRISMA flow diagram of our systematic review is shown in Figure 1.…”

“…Fourteen of the identified studies used psilocybin (Anderson et al, 2020; Bogenschutz et al, 2015, 2022; Carhart-Harris et al, 2016, 2021; Davis et al, 2021; Goodwin et al, 2022; Griffiths et al, 2016; Grob et al, 2011; Johnson et al, 2014; Moreno et al, 2006; Ross et al, 2016; Schneier et al, 2023; Sloshower et al, 2023), nine used MDMA (Bouso et al, 2008; Danforth et al, 2018; Mitchell et al, 2021; Mithoefer et al, 2011, 2018; Monson et al, 2020; Oehen et al, 2013; Ot’alora et al, 2018; Wolfson et al, 2020), eight used LSD (Gasser et al, 2014; Grof et al, 1972; Holze et al, 2022; Kast, 1967; Kurland et al, 1971; Mccabe et al, 1972; Pahnke et al, 1969; Savage and McCabe, 1973), three used ayahuasca (Osorio et al, 2015; Palhano-Fontes et al, 2019; Sanches et al, 2016) and three used DPT (Grof et al, 1972, 1973; Richards et al, 1977). No article using DMT, mescaline or ibogaine met our inclusion criteria.…”

History repeating: A roadmap to address common problems in psychedelic science

“…The breaking blind problem is therefore the rule rather than the exception in psychedelic trials (Muthukumaraswamy et al, 2021). For instance, in a recently published placebo-controlled study, 15 of 19 participants correctly guessed they had received a placebo, while 12 of 15 participants correctly guessed they receive an active dose after a medium-to high-dose psilocybin session (Sloshower et al, 2023; unfortunately they did not report the clinicians' guesses about treatment allocation). This threatens internal validity and the conclusions that can be drawn based on clinical studies for several reasons.…”

Psilocybin history, action and reaction: A narrative clinical review

“…In summary, our review of the literature on the efficacy of psilocybin-assisted treatments for psychiatric disorders and SUDs points to mixed results with early promise for certain disorder types. The strongest efficacy data until now is for psilocybinassisted treatment in the depression and anxiety disorders (Agin-Liebes et al, 2020;Sloshower et al, 2023;Thomas et al, 2017). However, interpreting this data is complicated by the lack of good placebo conditions for hallucinogen-based treatments and problems with generalizability of study populations for depression/anxiety RCTs, half of which were conducted in patients with end-of-life cancer diagnoses (Thomas et al, 2017).…”