Psilocybin-Assisted Cognitive Behavioral Therapy for Adults with Major Depressive Disorder: Rationale and Treatment Development

Abstract

Background:

Recent studies suggest that one to two administrations of psilocybin have acute antidepressant effects for people with major depressive disorder. These data on psilocybin have generated considerable enthusiasm, but little empirical attention has been paid to the therapy that adjoins psilocybin treatment (psychedelic-assisted therapy, or PAT).

Materials and Methods:

In this study, we present the initial protocol and plans to empirically test the psychosocial therapy that adjoins psilocybin treatment with the goal of optimizing this therapeutic approach for adults with major depressive disorder. The psychotherapy is based on the principles of cognitive-behavioral therapy (CBT), an evidence-based treatment for major depressive disorder. Participants will be 30 adults with a history of major depressive disorder and current, active depressive symptoms. Following psychiatric and medical safety evaluations, eligible participants will be enrolled in a 12-session CBT that includes classic PAT safety elements (termed psilocybin-assisted CBT; PA-CBT). Following the third and sixth PA-CBT sessions, participants will engage in two psilocybin drug administration sessions (10 and 25 mg, respectively). Participants will provide feedback about the PA-CBT and complete measures of mood symptoms, psychosocial functioning, cognitive schemas, and affective experiences immediately following each drug administration session, at the completion of PA-CBT, and 3 months following treatment completion.

Conclusions:

The trial will provide preliminary data on the feasibility, safety, acceptability, and psychosocial effects of PA-CBT. Results will inform randomized clinical trials to test the effects of PA-CBT for patients with depression and other mental health conditions, as well as hypotheses concerning mediating mechanisms at the cognitive and affective levels. ClinicalTrials.gov ID: NCT05227612.

Introduction

Psilocybin has emerged as a potential pharmacotherapy for a range of mental disorders, including alcohol use disorder,^1,2 smoking cessation,³ obsessive-compulsive disorder,⁴ cancer-related anxiety,⁵ and depression (e.g., Refs.^6,7). Specific to the trials for depression, one to two administrations of psilocybin (in dosages of 10–30 mg) along with varying degrees of supportive therapy produce antidepressant effects in individuals with major depressive disorder and those with treatment-resistant depression (i.e., individuals not responding to >2 trials of antidepressants).

These studies indicate an impressively large effect size for psilocybin treatment over up to 1 year post-treatment compared with placebo (Hedge's g's: 0.8–1.4), which is about 1.5–2 times the effect of psychotherapy or standard antidepressant medications for major depression.^8–10

More recently, however, the largest psilocybin study to date for the treatment of major depression found only modest treatment effects.¹¹ The beneficial effects for depressive symptoms were only present for a few weeks and not sustained at the 4-month follow up.

In addition, there were more adverse events (77%), ranging from mild events (e.g., headaches, nausea, dizziness) to suicidality, compared with previous studies.^6,7 Notably, Goodwin et al. provided three preparatory sessions before the drug experience and only two integration sessions after the drug experience.

To date, clinical trials with psilocybin have included wide-ranging psychotherapeutic support, from a couple of integration sessions to upwards of a dozen supportive therapy sessions.^7,11 The degree to which Goodwin et al.'s modest long-term effects and adverse responses to the drug may have to do with the minimal psychosocial therapeutic support that was provided remains unclear.

The psychosocial treatment adjoining psilocybin pharmacotherapy to date is psychedelic-assisted therapy (PAT), which involves some degree of preparation before the drug administration session(s) and varying numbers of integration sessions following the drug's administration to help the participant learn from the drug experience and attempt to implement these lessons within their life.

PAT's typical integration involves supportive therapy that culls from various traditions, including Rogerian person-centered therapy, “inner intelligence healing” (a theoretical orientation that asserts that living systems are inclined to reestablish equilibrium when provided the proper conditions), and Maslow's theory of self-actualization.¹²

Across the varying PAT approaches, psilocybin sessions are believed to create the conditions for depressed individuals to identify what they need to recover, and the integration sessions thereafter are led by the patient to enact those practices that will ultimately lead to their recovery. Although the various components of PAT are considered useful in facilitating a positive response to psilocybin and reducing the likelihood of adverse events,¹³ PAT has not been standardized or empirically tested. Potentially, providing standardized, evidence-based therapy may make treatment responses more durable with less adverse effects.

Cognitive behavioral therapy (CBT) is considered the gold-standard of empirically based psychosocial treatments for reducing depressive symptoms and decreasing the likelihood of relapse,⁸ and it may serve as a worthwhile standardized foundation for the integration of psilocybin treatment for patients with depression. First, CBT is a manualized treatment that has been widely tested and disseminated to clinicians.

Second, CBT's most profound effects are seen in its ability to buffer against depressive relapse.^14,15 CBTs (including third-wave therapies, such as Acceptance and Commitment Therapy) have been proposed as having the strongest rationale for serving as the psychosocial treatment component of psychedelic therapy;¹⁶ however, traditional CBT has not yet been tested as an adjunct to psilocybin for patients with depression.

Some of the mechanisms by which CBT is thought to buffer against relapse include its proximal clinical skills (e.g., assisting the patient in identifying cognitive distortions and maladaptive behaviors and engaging in more adaptive responses) as well as broader treatment targets (e.g., reducing maladaptive behavioral avoidance and cognitive rumination, improving emotion regulation and adaptive behavioral approach and/or acceptance).

The patient's alliance with their CBT therapist is another mechanism that leads to improvements in depressive severity and reduces the likelihood of relapse,^17,18 potentially by increasing the patient's willingness to adhere to the treatment. The CBT's action-oriented approach, providing tangible skills in sessions and encouraging between-session practice, may enhance the effects of psilocybin by motivating cognitive-behavioral changes, thereby instilling longer-lasting benefits. Moreover, CBT has a priori and testable targets, including improving emotion regulation, and reducing cognitive distortions.^19,20

Psilocybin may also help improve the efficacy of CBT. A pilot study of psilocybin as a treatment for tobacco addiction found that four sessions of CBT adjoined with the drug preparatory sessions provided higher rates of smoking cessation over a 6-month period compared with abstinence rates of similar-length CBT trials without psilocybin.³

Although current treatments for depression have clear efficacy, only about 40–50% of patients show a significant reduction in depressive symptoms^21,22 and relapse rates range from 23.6% to 36.8% over an 8- to 27-month period.²³ The negative beliefs of depressed individuals can become fixed, which, for some, makes CBT difficult to engage with or ineffective. Psilocybin engenders greater cognitive flexibility that leads to increased imagination and creativity.²⁴ Psychological flexibility, more generally (which includes cognitive, behavioral, and emotional flexibility to shift mindsets or behaviors to engage in adaptive behaviors²⁵), is associated with acceptance/avoidance experiences following psychedelic experiences.²⁶

Psychological flexibility has been shown to mediate the relationship between acute psychedelic effects of psilocybin and decreases in depression and anxiety.²⁷ Psilocybin also commonly creates mystical and awe experiences, which have been associated with reductions in depression and greater openness to new experiences.^28,29 The purported association between psilocybin and changes in cognition, motivation, and personality features make it a potential catalyst for the changes in thoughts and behaviors that are sought in CBT.

Although psychedelics have become a widely popularized topic within psychiatry, rigorous examination of psilocybin treatment and its various components (e.g., drug dose, inter-dose interval, the psychosocial therapy) remain unexplored. Of particular importance is the study of the adjoining psychotherapy as we expect that it is not the drug alone, but also the therapy enhanced by the drug that will produce the strongest and most durable effects.

In addition, with the exponential growth of published psychedelic data in the scientific literature, there is a significant need for an evidence-based, protocolized psychosocial treatment that can be disseminated to providers to use psilocybin effectively and safely for the treatment of mental health conditions.

We present our plans to protocolize and examine the feasibility, safety, acceptability, and initial effects of psilocybin-assisted cognitive behavioral therapy (PA-CBT) to begin the process of examining the psychosocial treatment(s) that adjoin psilocybin. The purpose of our investigation is to begin testing a manualized treatment that can be implemented and examined in randomized trials to improve the efficacy of psilocybin therapy and identify mechanisms of treatment action. Importantly, manualizing and testing the action of CBT, a well-delineated psychosocial treatment, may augment the effects of psilocybin on depression.

The study design is a single-group, fixed-dose trial in which we will recruit 30 participants with current active depressive symptoms (ages 21–60) who are physically healthy and not on any serotonergic medications. Eligible participants will undergo 12 individual sessions of PA-CBT over 4 months (9 weekly sessions followed by 3 biweekly sessions), during which two doses of psilocybin will be administered at a 1-month interval—a 10 mg dose following the third PA-CBT session and a 25 mg dose following the sixth session.

Two drug administration sessions are included in this design to incrementally step participants up to a high dose of psilocybin (25 mg) as well as to allow for an initial examination of the dose-specific effects of psilocybin on treatment outcomes. Participants will be followed for an additional 3 months following treatment termination. The clinical trial will follow previously well-established safety guidelines, including preparatory sessions before the drug administration and an integration session following each drug administration session.¹³

Primary aims and hypotheses

Our primary aim is to determine the feasibility, safety, and acceptability of adjoining CBT with PAT and psilocybin pharmacotherapy (PA-CBT). We hypothesize that psilocybin as an adjunct to 12 sessions of PA-CBT will be feasible (i.e., that patients can be recruited and retained for the full duration of the treatment), safe (i.e., comparable or fewer adverse events compared with prior psilocybin trials for depression), and reviewed favorably (i.e., high ratings of satisfaction and low levels of burden by participants and clinicians alike).

Secondary aims and hypotheses

We will examine the preliminary effects of the PA-CBT treatment on mood (i.e., clinician- and participant-rated depressive symptoms) and psychosocial functioning (i.e., clinician-rated global and clinical functioning) over 7 months. We hypothesize that the treatment will be associated with significant reductions in depressive symptoms and improvements in psychosocial functioning from pre-treatment to post-treatment (4 months) and at a 3-month post-treatment follow-up.

Exploratory aims

We will explore the preliminary effects of PA-CBT on modifying the following proposed treatment targets: cognitive schemas (i.e., cognitive distortions and openness to new experiences), emotional regulation, strong responses during the drug experience (i.e., mystical and awe experiences, psychological insights, challenging experiences), and the alliance between the patient and therapist. We will also examine whether changes in the following treatment targets correlate with changes in mood and psychosocial functioning.

We expect that the PA-CBT will reduce cognitive distortions, increase openness to new experiences, improve emotional regulation, and lead to increases in awe and mystical experiences, psychological insights, and challenging experiences. We expect these changes to be magnified for participants with strong alliances with their therapist. We further expect these changes to be associated with improvements in mood symptoms and psychosocial functioning over the 7-month study period.

Materials and Methods

Study screening and inclusion/exclusion criteria

The clinical trial has been approved by the University of California, Los Angeles (UCLA) Medical IRB and is being conducted at the UCLA Semel Institute for Neuroscience and Human Behavior. Participants will first be screened over the phone by a research assistant to determine preliminary eligibility for study criteria (i.e., participants must be between the ages of 21–60, meet lifetime criteria for a major depressive disorder, have current active depressive symptoms, be physically healthy, not be taking serotonergic medications, and not have a personal or family history of bipolar or psychotic disorders).

Specific to age, the study team decided to have a relatively conservative age inclusion to minimize health risks at upper ages and minimize psychiatric risk (e.g., risk of conversion to serious mental illnesses) at lower ages. Participants who appear to meet these preliminary eligibility criteria will be invited for a more comprehensive in-person psychiatric and medical screening. Participants will not be compensated for their participation; however, the treatment is provided at no cost. A schematic of the study design is presented in Figure 1 given next.

Fig. 1.

Participants enter the study following a phone screen. Eligibility to proceed to the PA-CBT is determined at the psychiatric and physical screen. Eligible participants continue through the PA-CBT and drug sessions. The curved-edged boxes indicate study assessments through the course of 7-month study. PA-CBT, psilocybin-assisted cognitive behavioral therapy.

Medical screening

The medical screening will include a general physical exam, an electrocardiogram, and a blood draw. Participants will be excluded if they report or are found to have any cardiovascular conditions. A personal history of stroke, Transient Ischemic Attack, hepatic impairment, epilepsy, and insulin-dependent diabetes will also be exclusionary. Patients with resting blood pressure above 140 systolic, 90 diastolic or heart rate >90 beats per minute will be excluded.

The medical screening will also include a urine drug screen to determine any current drug use (substance use disorders and use of illicit substances other than cannabis are exclusionary) and a urine pregnancy screen to rule out pregnancy in biological females.

Chronic and/or recent use of antidepressants (e.g., serotonin reuptake inhibitors) and other substances that affect serotonergic functioning can attenuate the effects of hallucinogens (Bonson, 2012; Strassman, 1992), and thus pose a scientific confound.^30,31 Participants will not be able to proceed past the study screening if/while they are currently on serotonergic agents, lithium, or efavirenz (regardless of whether the drug(s) is/are prescribed for a depressive disorder or another condition).

Psychological screening

Each participant will undergo a psychological evaluation with a study psychologist. The Structured Clinical Interview for DSM-5 (SCID-5)³² and a Family History Screening instrument³³ will be used to determine participants' personal and family mental health history. Eligible participants must have a current major depressive episode or a history of major depressive disorder.³⁴

Individuals with a personal or family history with psychosis will be withdrawn from the trial, as there is a risk that psilocybin can induce psychosis, particularly in patients with a predisposition for these conditions.³⁵ In addition, individuals with a Cluster B Personality Disorder (narcissistic, histrionic, borderline, and antisocial personality disorder) will be withdrawn during the screening process based on evidence suggesting that these individuals have a higher likelihood for negative hallucinogenic experiences.^36,37

Study clinicians will rate each participant on their depressive symptom severity using the Hamilton Depression Rating Scale (HAM-D³⁸). To be eligible, participants must have current, active depressive symptoms that are at least of moderate severity (score >16 on the HAM-D covering the prior 2 weeks) but cannot have active suicidality, as identified on the HAM-D and Columbia Suicide Severity Rating Scale,³⁹ or other psychiatric disturbance that requires acute treatment or alternative primary treatment as determined by the trial's lead investigators and/or psychiatrist (e.g., primary diagnosis of post-traumatic stress disorder or obsessive compulsive disorder).

Participants will be excluded if they meet DSM-5 criteria for substance use disorder within the prior 6 months, have used a psychedelic within the prior 12 months, or have ever had an adverse reaction to a psychedelic (i.e., physical or psychiatric complication requiring medical attention or causing significant distress as reported by the participant).

Participants who are receiving psychotherapy (other than CBT or other third-wave cognitive behavioral approaches) at the study entrance may participate if the frequency of the therapy has been stable for the past 2 months and is expected to remain stable during participation in the study. Because we are examining a specific model of psychosocial therapy, participants who are currently receiving CBT (or variant of CBT, including third-wave cognitive behavioral approaches) or have commenced a new psychosocial treatment within the past 2 months are not eligible.

Study clinicians

The clinicians conducting the screening interviews and serving as the therapists and/or drug session monitors in the PA-CBT are doctoral-level clinicians (psychiatrists and psychologists). The trial's lead psychiatrist (J.K.J.) has received certifications in PAT from multiple psychedelic training institutes. The trial's consulting psychiatrist (C.S.G.) has decades of experience conducting psychedelic clinical trials.

The lead psychiatrist and the consulting psychiatrist provided the other study clinicians with structured didactic training in PAT, and the co-PI (M.J.W.) provided structured didactic training on the CBT protocol before the launch of the trial. The lead psychiatrist and the consulting psychiatrist will serve as co-therapists for the first case, and the other study clinicians will observe for additional training.

The lead psychiatrist will then serve as co-therapist with the co-PI until he is able to serve independently as a lead clinician. The co-PI and the lead psychiatrist will be the primary clinicians for this trial, with secondary assistance from three other doctoral level clinicians.

Psilocybin drug administration sessions

Two drug administrations will be conducted—the first drug administration session (10 mg dose) will be conducted over a 6-h period and the second, high-dose session (25 mg) will be conducted over an 8-h period. The first drug administration will be conducted following the third psychotherapy session; the second will be conducted following the sixth session. We decided to include a smaller-dosed first session to allow participants to build up to the high-dose session.

We believe this will allow the participants to have greater comfort with the higher dose. It will also assist the research team in examining (qualitatively) whether there are any measurable effects of a smaller dose in modifying cognitions, emotions, behaviors, and/or psychiatric symptoms. We decided to deliver the first drug session after the third session, as we sought to maximize the number of integration sessions following the drug experiences.

In addition, the second drug session was positioned approximately a month after the first drug session to allow for the initial presentation of CBT principles and skills. The protocol for both drug session administrations will follow the procedures that have been set forth by the Johns Hopkins University psychedelic research group (i.e., participant laying on a couch with eyeshades and listening to classical music).¹³

PA-CBT psychotherapy

The psychotherapy will be conducted over a 4-month period and adapted from the Unified Protocol for emotional disorders.^40,41 Consistent with the number of therapy sessions in the vast majority of CBT interventions for depression,^8–16,42 this trial will include 12 sessions of psychotherapy. The first nine sessions were held weekly, and the final three sessions were held biweekly.

The treatment will include the classic PAT preparatory sessions in the first three sessions as well as open-ended integration in each session following the two drug administration sessions. The remaining seven sessions will be dedicated to CBT. We provide a more detailed outline of the treatment next, and a brief overview of the PA-CBT session content is presented in Table 1.

Table 1.

Session-by-Session Summary of the Psilocybin-Assisted Cognitive Behavioral Therapy

Session	Title	Session content
1	PAT—Psilocybin Preparation	Build rapport with participants Learn about their “story” Psychoeducation about psilocybin Present ideas of inner healing intelligence
2–3	PAT—Psilocybin Preparation continued	Review drug session protocol and helpful responses to drug session Discuss therapeutic touch and consent for therapeutic touch Co-therapist for drug session meets with participant and primary therapist Set intention for drug administration sessions Lead participant through guided meditation
	Drug administration session no. 1 (10 mg)	Participant conducts urine screen before drug administration session Therapists review intention and drug administration session protocol Participant is given 10 mg psilocybin, encouraged to lay down with eye mask and listen to pre-set music Drug administration session lasts ∼6 h Participant completes study questionnaires Following safety check, participant is released to family member or friend
4	PAT—Open-ended Integration	Assess for persisting adverse events of psilocybin Develop the patient's narrative of drug experience Discuss emotional and cognitive process of drug administration session based on BME categories
5–6	CBT—Behavioral Activation and Opposite Action	Present CBT theoretical rationale (CBT triangle) Present the cycle of avoidance in depression Discuss value/rationale of doing opposite of unhelpful behavior(s) Develop specific, measure Opposite Action goals (e.g., behavioral plan, hierarchy)
	Drug administration session no. 2 (25 mg)	Participant conducts urine screen before drug administration session Therapists review intention and drug administration session protocol Participant is given 25 mg psilocybin, encouraged to lay down with eye mask and listen to pre-set music Drug administration session lasts ∼8 h Participant completes study questionnaires Following safety check, participant is released to family member or friend
7	PAT—Open-ended Integration	Assess for persisting adverse events of psilocybin Develop the patient's narrative of drug experience Discuss emotional and cognitive process of drug administration session based on BME categories Link cognitive insights and emotions to therapy intentions/goals
8–9	CBT—Continuation of Behavioral Skills+Cognitive Skills	Re-present CBT rationale Present common “thinking traps” (i.e., cognitive distortions) Help participant to identify link between thoughts, feelings, and behavior Present detective thinking (i.e., cognitive reappraisal) to have participant modify unhelpful thoughts Develop the participants' ability to think flexibly about emotional situations As needed/desired, present mindful acceptance as cognitive skill
10–11	CBT—Relapse Prevention Plan	Discuss relapse as common experience of depression and maintenance of coping skills as important to reduce likelihood of relapse Review domains of difficulty (recall BME questionnaire) Review specific unhelpful thoughts, behaviors, cycles of avoidance/approach Review coping strategies (coping thoughts and behaviors) Put together the above in the relapse prevention handout
12	Treatment Review and Termination	Review themes from therapy, including areas of difficulty that were focused on as well as coping strategies developed Make plan for participant to maintain skill practice following treatment termination Discuss the participant's next steps (e.g., goals, areas of focus) following treatment termination

BME, body-mind-environment; CBT, cognitive behavioral therapy; PAT, psychedelic-assisted therapy.

To help facilitate the psychotherapy, before the first session, the participant will be asked to conduct a holistic psychosocial review of their life via our internally created “Body-Mind-Environment” questionnaire, which was adapted from Bourzat and Hunter's “Holistic Model for a Balanced Life: An Inventory.”⁴³

This open-ended questionnaire includes specific questions about a range of domains, including emotional well-being, physical well-being, cognitions, social and spiritual life, and connections to nature and community. By completing this questionnaire before the start of the psychotherapy, we expect that the participant will be more easily able to identify goals and actionable steps to improve their depression on starting treatment.

PAT sessions

The first three sessions (i.e., preparation module) of the psychotherapy protocol focus on preparing the participant for the drug administration sessions. These first three sessions represent the part of PAT that has become typical in the psilocybin therapy empirical literature to increase the likelihood of a safe and positive experience.¹³

In the first therapy session, the therapist will work to build rapport and learn about the participant's psychosocial background and presenting difficulties. Ideally, this conversation will be aided by the thoughts that were spurred by the Body-Mind-Questionnaire. The participant will also be presented with psychoeducation regarding the effects of psilocybin and some of the theoretical rationale underlying the value of psilocybin for treating depression.

Participants will be oriented to psilocybin as a tool for helping work toward recovery (i.e., not as a panacea, but one component of the treatment). The participant will be led to understand that psilocybin has wide-ranging effects, which include the ability to expand or alter our thoughts and perceptual experiences. The participant and therapist will discuss how, through these alterations, the participant will hopefully be better able to modify and maintain more helpful cognitions and behaviors.

In the second and third sessions, the therapist presents the protocol for the drug administration sessions (see next for more information). The therapist will also engage the participant in best practices for managing the effects of psilocybin, particularly if they become intense or overwhelming.

The participant will be told that the ultimate goal for them if they feel distressed by the drug experience is to remember that (1) what they are experiencing is because of the drug and (2) it is time limited. In addition, the participant will be encouraged to approach their internal experiences (as opposed to avoid or turn away from these experiences).

Psychoeducation about the cycle of avoidance as a maintenance factor for depression and the goal of approaching adaptive thoughts and behaviors will be presented. These concepts will serve as an important foundation for managing stressful experiences during both the psilocybin drug sessions and the CBT skill practices. This approach strategy is consistent with CBT principles and has been proposed to be a mechanism by which PATs can produce therapeutic change in mental disorders.⁴⁴

When necessary, the participant can be engaged in a relaxation exercise (e.g., deep breathing, progressive muscle relaxation), which will be taught in the preparation sessions before the psilocybin sessions.

In the third session, the participant will meet the secondary clinician who will be joining to assist for the drug administration sessions. The clinicians will guide the participant through a guided meditation (e.g., progressive muscle relaxation). The clinicians will also discuss therapeutic touch and consent for therapeutic touch. Therapeutic touch in the context of psychedelic therapy is commonly used to help provide support to the participant; however, as in all psychotherapeutic relationships, is done only with consent, in specific non-imposing areas (e.g., shoulder, forearm, hand), and must never be done in any sexual or imposing manner.

Finally, and importantly, the clinicians will work with the participant to develop their intention(s) for the drug administration session. The intentions for the drug administration session pertain to why the participant is taking the drug, what they hope to learn or experience, and what they hope the experience can do for their depression and their life overall.

The fourth and seventh therapy sessions will be conducted within a day or two after the first and second psilocybin sessions, respectively. These sessions are considered open-ended integration sessions, as they will not focus on CBT skills, but instead follow the classic PAT-style supportive therapy integration. These sessions will first involve checking in with the participant about any adverse events related to the psilocybin experience, including suicidality, persisting headaches, or perceptual abnormalities.

The bulk of the session will then focus on exploring the participant's drug experience. The therapist will first allow the participant to explore their drug experience in an open-ended format to begin to develop a narrative of their experience. The goal will be for the participant to identify emotions that arose and any cognitive insights and then to attempt to relate any of these experiences back to their intentions for the drug administration session and areas of focus developed from the initial sessions of therapy (e.g., Body-Mind-Environment questionnaire).

For example, a participant may express an intention for the drug administration session to inform their recovery from depression and then report profound feelings of calmness and acceptance of their life from the drug administration session, and they might be asked to consider how those feelings of calmness and acceptance might be helpful thoughts/responses to combat their depression.

CBT integration sessions

The fifth and sixth sessions begin the start of CBT. The participant will be provided psychoeducation regarding the cognitive-behavioral model for depression (i.e., the effects of cognitive distortions and unhelpful behaviors on mood and the cycle of avoidance) and the theoretical rationale for CBT. Next, the participant and therapist will work together to develop specific, measurable goals.

These sessions will prioritize the elaboration of the participant's goal(s) and outlining actionable steps for the participant to take toward those goals. The participant will then be taught and directed to engage in behavioral skills, including scheduling pleasant events, behavioral activation, and/or opposite action (i.e., engaging in the opposite behaviors of their habitual unhelpful behavior).

As much as possible, any insights gleaned from the psilocybin experience will be used to help promote the participant's actions toward their goal. In addition, the parallel between how to manage the psilocybin experience and how to respond to their depression will be made clear. To increase the likelihood of a beneficial experience with psilocybin, the participant will be encouraged to approach (as opposed to avoid) what comes up during the drug administration session.

Similarly, the participant will be encouraged to engage in more approach tendencies behaviorally, be it through pleasant events scheduling, behavioral activation, and/or opposite action.

In the eighth and ninth sessions, the behavioral skills will be further elaborated and implemented. The participant and therapist will review the behavioral progress made and make further behavioral goals and plans. The participant will also be presented with cognitive skills, including thought monitoring, identifying cognitive distortions (i.e., “thinking traps”), and conducting cognitive restructuring.

To help participants think more flexibly, mindfulness-based cognitive skills may also be presented to the participant. Insights that were gleaned and alternative cognitions that were produced during the drug administration session that appear relevant for the participant's treatment will be reviewed and discussed.

The link between these thoughts and the participant's emotions and motivations will be also discussed. Considering that the psilocybin experience will likely produce cognitive alterations, the experience will likely prove useful in validating the CBT theory that changes in thoughts can produce changes in emotions and behaviors. Further, these altered thoughts will be leveraged to help the participant align with new cognitions as well as promote additional desired behavioral change.

The tenth and eleventh sessions will involve the continuation of cognitive-behavioral skill implementation. The participant will also be guided in the production of a relapse prevention plan to outline early warning signs for a depressive episode and coping strategies to buffer against mood relapse.

Since relapse is a common in the course of depression,⁴⁵ the maintenance of coping skills will be emphasized. The final session will review treatment gains, treatment themes, and the relapse prevention plan and discuss next steps following treatment termination. Although we intend for the psychosocial therapy to be 12 sessions, this treatment development study will allow for flexibility in the protocol so that the research team can optimize a psilocybin-based CBT, including the possibility of adding sessions or reducing the treatment length.

Outcome assessments

Study assessments will be held before starting the PA-CBT (i.e., baseline), following each drug administration session, at the PA-CBT's completion, and 3 months following the treatment's completion. The trial's primary outcomes will include measurements of feasibility (e.g., recruitment, attrition, retention) as well as the participants' and clinicians' qualitative and questionnaire-based views of the acceptability and burden of the psychosocial and drug treatments at the post-treatment and 3-month follow-up assessments.

Secondary outcomes will include depressive symptom severity with the Hamilton-Depression Inventory, the Columbia Suicide Severity Rating Scale, and the Patient Health Questionnaire 9,⁴⁶ collected at the baseline assessment, post-treatment, and 3-month follow-up assessments. In addition, the Profile of Mood States Questionnaire will be used to measure same-day mood at each assessment.⁴⁷

Overall functioning over the 2 weeks before the assessment will be assessed with the 100-point Global Assessment of Functioning Scale⁴⁸ and the Clinical Global Impressions⁴⁹ at the baseline assessment, post-treatment, and 3-month follow-up assessments.

For exploratory purposes, to assess whether there are changes in cognitions and emotional responses, we will use the Brief Core Schema Scale⁵⁰ and Difficulties with Emotion Regulation Scale,⁵¹ and we will measure changes in personality traits using the Big Five Inventory⁵² at the baseline assessment, post-treatment, and 3-month follow-up assessments. Following each drug experience, we will also measure participants' mystical experiences and changes of consciousness via the Altered States of Consciousness Questionnaire,⁵³ the Awe Experience Scale,⁵⁴ the Challenging Experiences Questionnaire,⁵⁵ Psychological Insight Questionnaire,⁵⁶ and the Revised Mystical Experiences Scale.⁵⁷

At the end of therapy sessions before each drug administration session (sessions 3 and 6) and at the post-treatment assessment, we will measure therapeutic alliance from both the patient and therapist perspective using the Helping Alliance Questionnaire II.⁵⁸ The trial will terminate following the 3-month follow-up assessment.

Data analysis plan

For primary study aims, we will ascertain feasibility through the following metrics: recruitment totals (i.e., participants telephone screened, screened eligible following medical and psychological screen, and participants consented) and retention/attrition of participants throughout the 7-month study period.

The occurrence and details of adverse events will be gathered via clinician interview at the end of both drug administration sessions and at each open-ended integration session following both drug sessions (adverse events inquired about include headaches, other physical discomfort, perceptual abnormalities, emotional distress, deliberate self-injury, suicidality, hospital visit/hospitalization, contact with police, work/school problems).

We will also score mean levels of satisfaction with various components of the treatment using a study-specific questionnaire (e.g., length of treatment, doses of psilocybin). We will also qualitatively gather and analyze participant and clinician feedback regarding the treatment and drug protocols.

For secondary and exploratory analyses, we will use repeated-measures mixed modeling to examine the changes of depressive symptoms, psychosocial functioning, and exploratory variables over the course of the trial. If data are not missing at random (e.g., more items are missing in male than female participants), we will covary baseline variables (in this case, sex) that account for missingness.

We will then examine the correlations of secondary variables with proposed exploratory variables over the active treatment period and the 7-month study overall.

Discussion

Although CBT has been examined as an adjunct to ketamine therapy for major depression,^59,60 this is the first examination, to our knowledge, of adjoining CBT with psilocybin treatment for depression. We plan to operationalize a structured, manual-based PAT that adjoins psilocybin drug treatment.

An evidenced-based psilocybin therapy manual will increase the coverage and disseminability of this cutting-edge treatment for those suffering from depressive disorders. We will also examine the feasibility, safety, acceptability, and psychosocial effects of PA-CBT.

Study results will lay the foundation for future research to investigate methods to improve the efficacy of CBT when paired with psilocybin, improve psilocybin treatment, as well as examine psilocybin's comparative effects to other drugs. We ultimately expect that CBT and psilocybin will work synergistically to improve the efficacy of both treatments for patients with depression.

We acknowledge several limitations to our trial's design. First, there is no comparator to the PA-CBT condition. Although we ultimately would like to compare PA-CBT with comparators (e.g., CBT without psilocybin, psilocybin with standard PAT), this trial is conceptualized as a treatment development study to assess the feasibility, safety, acceptability, and preliminary effects of the treatment.

Thus, we will not be able to make any conclusions about the efficacy of PA-CBT from this preliminary study. In addition, the sample will be modest (N = 30). However, we expect that the sample will provide a preliminary indication of the signal for our hypotheses.

The trial will also be limited by the strict inclusion/exclusion criteria. By excluding individuals who are not physically healthy and/or taking serotonergic medication(s), it will remain unclear as to how the study therapies will affect those populations. Similarly, it will remain unclear as to how the treatments will affect older and younger populations.

There is some evidence that psilocybin can be beneficial for older and physically ill populations;^5,61 however, very few older adults or patients with serious comorbidities have been included in psychedelic clinical trials. We felt it important to limit the study population to increase the likelihood of safety within the trial and solidify the treatment procedures.

Future directions include larger-scale randomized controlled trials (RCTs) comparing psilocybin treatment with various intensities and modalities of psychotherapy. These larger trials will help to fine-tune the psychotherapy that adjoins psilocybin treatment. In addition, these RCTs will help elucidate the degree to which it is the drug (and at what dose), the psychotherapy (and at what intensity), or their combination is producing psychiatric and functional benefits.

Modifying each of these variables will be also important for our understanding of the therapeutic benefits of psilocybin therapy and to better personalize these treatment approaches. Although psilocybin appears to be a potent medicine, empirical research identifying treatment targets, and mediators and moderators of outcomes will help uncover the underlying mechanisms of the treatment.

Authors' Contributions

M.J.W.: study conceptualization (lead); methodology (lead); writing—original draft (lead); and review and editing (equal). J.K.J.: study conceptualization (supporting); methodology (supporting); and writing—review and editing (equal). C.S.G.: methodology (supporting); writing—review and editing (equal). M.C.I.: methodology (supporting); writing—review and editing (equal). R.L.B.: methodology (supporting); writing—review and editing (equal). Z.D.C.: methodology (supporting); writing—review and editing (equal). D.J.M.: study conceptualization (supporting); methodology (supporting); and writing—review and editing (equal).

Author Disclosure Statement

The authors declare no conflicts of interest. M.J.W. receives support from the National Institute of Mental Health (NIMH), Brain & Behavior Research Foundation, Friends of Semel, and the American Psychological Foundation. J.K.J. has no declarations of interest. C.S.G. receives research support from The Heffter Research Institute, The Multidisciplinary Association for Psychedelic Studies (MAPS), and The Steven and Alexandra Cohen Foundation. He serves on the Scientific Advisory Panel of Lobe Sciences. M.C.I. reports support from the Max Gray Fund. R.L.B. has no declarations of interest. Z.D.C. reports receiving study drug from Canopy Growth Corp and True Terpenes, and study-related materials from Storz & Bickel. She served a scientific consultant for Canopy Growth Corporation in 2021 and on the scientific advisory board for FSD Pharma in 2020. Z.D.C.'s research is funded by grants from the National Institute on Drug Abuse, National Center for Complementary and Integrative Health, California Department of Cannabis Control, Center for Medicinal Cannabis Research, and the California Highway Patrol. D.J.M. receives research support from the NIMH, the Danny Alberts Foundation, Attias Family Foundation, Carl and Roberta Deutsch Foundation, Kayne Family Foundation, AIM for Mental Health, and Max Gray Fund, and book royalties from Guilford Press and John Wiley and Sons.

Funding Information

Funding for this study is provided by the UCLA Semel Institute for Neuroscience and Human Behavior and the Brain & Behavior Research Foundation.