Methodological challenges in psychedelic drug trials: Efficacy and safety of psilocybin in treatment-resistant major depression (EPIsoDE) – Rationale and study design

This paper (2022) details the rationale and study design for an upcoming double-blind placebo-controlled trial (n=144) which will assess the safety and efficacy of using psilocybin in a cohort with treatment-resistant depression.

Abstract

“Psychedelics such as psilocybin have recently gained remarkable interest in both the specialist literature and the lay press because studies suggest that these substances may have great therapeutic potential in various psychiatric disorders, including major depression. However, clinical trials with psychedelic drugs pose particular methodological challenges to researchers, some of which differ considerably from those with other psychotropic drugs. These include the problem of successful blinding, which can hardly be guaranteed in clinical trials with psychedelic substances and – directly related – the high risk of expectation bias and nocebo effects. Some of these challenges are being addressed in the given clinical trial on the efficacy and safety of psilocybin in treatment-resistant major depression. It is a phase II randomized, double-blind, active placebo-controlled parallel-group trial with 144 patients. The rationale, the study design, and the core features of the study are presented here. The trial (EPIsoDE trial; EudraCT number: 2019-003984-24; NCT04670081) is funded by the German Federal Ministry of Education and Research (BMBF 01EN2006 ​A/B).”

Authors: Lea J. Mertens, Michael Koslowski, Felix Betzler, Ricarda Evens, Maria Gilles, Andrea Jungaberle, Henrik Jungaberle, Tomislav Majic, Andreas Strohle, Max Wolff, Stefan Wellek & Gerhard Grunder

Summary

Psychedelics have recently gained remarkable interest in both the specialist literature and the lay press because studies suggest that they may have great therapeutic potential in various psychiatric disorders, including major depression. However, clinical trials with psychedelic drugs pose particular methodological challenges to researchers.

1. Introduction

Classical psychedelics, including lysergic acid diethylamide (LSD) and psilocybin, represent one of the most innovative and promising treatment approaches in contemporary psychiatric research. However, most studies are open-label or uncontrolled, and the single available double-blind trial against an active comparator lacks statistical power.

Clinical trials initiated by academic investigators can have methodological issues, including the difficulty of blinding studies on psychedelic drugs.

Here we report the design of a phase IIb study on psilocybin in treatment-resistant major depression. The study addresses some methodological issues raised by the clinical assessment of psychedelic drugs.

2.1. Study design

A bi-centric, prospective, randomized, double-blind, active placebo-controlled parallel-group study was conducted in patients with TRD to investigate the effects of a high-dose psilocybin (25 mg) and a low-dose psilocybin (5 mg) versus an active placebo (100 mg nicotinamide).

2.2. Objectives and hypotheses

We expect significant and stable treatment responses after 25 mg of psilocybin, while provoking only mild and transient adverse events. We also expect to find potential neurobiological and psychological therapeutic mechanisms of psilocybin treatment.

2.2.1. Primary objective

The primary endpoint is treatment response, which is defined as a reduction in the total score of the German Hamilton Rating Scale for Depression (HAM-D) by at least 50% six weeks after the first dosing session.

2.2.2. Secondary objectives

Safety measures are assessed on each dosing day, one day after each dosing, and at both follow-up assessments. Additionally, the question whether a second putatively therapeutic high-dose is superior to only one high-dose is tested.

The treatment response differs between nicotinamide, 5 mg psilocybin and 25 mg psilocybin six weeks after the first dose, and the treatment response manifests already one day (BDI-II only) and one week after administration of 100 mg nicotinamide, 5 mg psilocybin, or 25 mg psilocybin.

2.2.3. Additional objectives

Additional outcomes assessed in an exploratory, some in an hypothesis-driven manner, include post-treatment changes in inflammation and neuroplasticity markers, cortisol levels, subjective sleep quality, resilience, sexual functioning, the sense of purpose or meaning in life, anhedonia, experiential avoidance, trait mindfulness, sense of free will, and personality profiles.

We examine the role of genetic factors, epigenetic markers, microbiome changes, women’s luteal phase and gender on treatment response, as well as patients’ subjective experience throughout the treatment process.

Key inclusion criteria are being medically stable, abstinence from monoaminergic psychiatric medications for at least 2 weeks before the first dosing, and giving informed consent. Key exclusion criteria are having a current substance use disorder.

2.4.1. Recruitment and screening

After an initial telephone or video screening, two in-person screening visits are scheduled. During these visits, patients are informed about the Investigational Medicinal Products and are down-titrated of their psychiatric medication if necessary.

2.4.2. Treatment phase

During visit 2, the patient is prepared for the psychedelic experience by discussing expectations, setting a therapeutic intention, and being introduced to strategies for handling potential challenging experiences. The patient visits the therapy room, music is introduced, and eyeshades are introduced.

The patient is administered an IMP in the early clinical trials unit of the CIMH and an equivalent setting at the CCM. Vital signs are monitored during the entire treatment session and two blood samples are taken for determination of psilocin serum concentrations at 2 h and 3 h post dosing, respectively.

In case of challenging or stressful experiences, therapists provide a sense of safety, encourage the patient not to resist, and ask the patient to write a detailed report of his/her dosing session experience.

The day after treatment, the patient has a post-acute integration session with his/her therapists to work through and integrate the past experience. Blood samples are taken, and vital signs are measured.

Patients are contacted by their therapists by phone on a weekly basis after each dosing session to assess potential adverse events and suicidality.

2.5. Investigational medicinal product

The study uses psilocybin freebase and 25 mg capsules, which are provided according to Good Manufacturing Practice (GMP) guidelines by the Usona Institute, USA, and synthesized by Almac Group, UK. The study uses a dynamic randomization procedure using Efron’s biased-coin method.

The clinical trial was conducted in accordance with the Declaration of Helsinki, the German Medicines Act, and the Good Clinical Practice (GCP)-guideline. It received favorable opinions from several ethics committees and was approved by the competent authority.

2.7.1. Sample size calculation and power analysis

After 6 weeks, the response rate to a single dose of 25 mg psilocybin or 5 mg nicotinamide is assumed to be 50%, 20% and 10%, respectively, based on the existing literature on the pharmacological treatment of TRD.

Using Boschloo’s power-improved version of the exact Fisher test, the sample sizes required to attain a power of 98.5% in the preliminary test of superiority of 25 mg psilocybin over nicotinamide are computed to be n 1 443 per treatment group. If 10% of patients drop out, the sample size per treatment arm has to be increased to 43 10/9 48 patients. A closing visit is scheduled, including thorough assessments of safety and efficacy endpoints.

2.7.2. Primary efficacy analysis

The confirmatory statistical analysis of the primary efficacy endpoint will be done by means of standard maximum-likelihood techniques for inference in logistic regression models. The tests will be carried out on an intention-to-treat (ITT) basis, at one-sided significance level 1 4 0.025 and embedded in a multiple testing procedure involving two tests to be carried out in fixed order.

2.7.3. Secondary efficacy analysis

The secondary objectives will be addressed by a mixed-effects linear model fitted by restricted maximum-likelihood (REML) estimation to the total HAM-D scores measured at 1, 6 and 12 weeks after the first dose. The additional nonrandom co-variables contained in the model will be the same as in the logistic model used in the confirmatory part of the analysis.

3. Discussion

The study addresses several crucial methodological questions in psychedelic drug trials, such as unblinding and nocebo effects, and expectation bias.

Clinical trials of psychotropic drugs usually compare the experimental drug to a placebo and/or an active comparator with proven efficacy in that same indication. However, the response rate and dropout rate in RCTs are clearly modulated by patients’ and therapists’ expectations.

In clinical trials, clinicians and patients have different expectations, and this influences the magnitude of symptom reduction. When investigators are blind to the trial design, the difference between treatment conditions becomes small.

The study by Carhart-Harris et al. comparing psilocybin with the standard antidepressant escitalopram was not sufficiently powered to exclude a statistical type-2 (beta) error, and the results were interpreted in a way that was inconsistent with the existing evidence from studies with antidepressants. Patients usually self-register for trials with psychedelics, and due to the subjective effects of these substances at high doses, blinding of treatment with a classical psychedelic is extremely difficult in an RCT.

The disappointment about not being in the psilocybin condition was evident in the first dosing session, before the first escitalopram pill was taken.

In studies of psychedelics with active comparators, a “real” placebo condition is required, and treatment with a potentially effective, high dose of the psychedelic should be offered to every patient randomized after assessment of the primary endpoint. In our study, two-thirds of patients were excluded from measurement of the primary endpoint due to disappointment at not having received the supposedly effective, high dose of psilocybin. This prevented artificially increasing the dropout rate in the treatment arms with patients who had received the supposedly less or ineffective treatment. Patients who have made numerous unsuccessful attempts at treatment should be offered psilocybin, since one-sixth of patients receive the high dose twice.

Attempts have been made to address the problem of blinding in studies with psychedelics by administering so-called active placebos or low, potentially ineffective doses of the test substance as comparators. A compound called niacin, which causes peripheral side-effects such as flushing, itching or tingling and abdominal discomfort, was used as an active placebo in a study published in 2016. The stimulant methylphenidate has been used to blind the effects of psilocybin in healthy volunteers, but patients can relatively easily distinguish them even from psychoactive active placebos. Griffiths et al. (2016) administered psilocybin to patients with life-threatening cancer and symptoms of depression and/or anxiety, and called the low dose “placebo-like”. They chose the 5 mg-dose as a supposedly therapeutically ineffective dose, while assuming that subjective effects will be noticeable to most patients.

The question of whether a profound psychedelic experience is necessary for a long-term therapeutic effect is central to all treatment research with psychedelics. The methodological challenge is substantial and possibly even unsolvable, because there is no other field in pharmacology in which the therapeutic effect seems to be linked as much to the subjective experience of the effect.

Contributors

LM, GG and SW designed the study, and GG and LM are coordinating the trial. All authors provided expert advice.