Psilocybin in Chronic Low Back Pain and Depression

Changes in positive affect as assessed by discrete positive affect items and averaged over 7-day periods of Ecological Momentary Assessment (EMA)

Discrete positive affect items: joy, love, hope, contentment. Positive affect will be assessed by asking participants to rate the intensity of four discrete positive emotions (joy, love, hope, contentment) on a 5-point Likert scale from 1-5 ("Very slightly or not at all" to "Extremely") and averaging those discrete items. Positive Affect scores will be aggregated over 7-day EMA periods at baseline, post-session, and 1-month follow-up. Higher Positive Affect scores represent higher levels of positive affect. A separate set of linear mixed-effects models (LMERs) will be utilized for each primary endpoint (aggregated averages of momentary positive affect), with a primary LMER estimating the difference between Baseline and Week 1. The Time x Group interaction will be the primary focus, and we aim to evaluate 1) the extent to which the primary endpoint differs between Baseline and Week 1, and 2) the extent to which that difference varies between the Psilocybin and Control groups.

Changes in negative affect as assessed by discrete negative affect items and averaged over 7-day periods of Ecological Momentary Assessment (EMA)

Discrete negative emotion items: depressed, angry, frustrated, and worried. Negative affect will be assessed by asking participants to rate the intensity of four discrete negative emotions (depressed, angry, frustrated, and worried) on a 5-point Likert scale from 1-5 ("Very slightly or not at all" to "Extremely") and averaging those discrete items. Negative Affect scores will be aggregated over 7-day EMA periods at baseline, post-session, and 1-month follow-up. Lower Negative Affect scores represent lower levels of negative affect. A separate set of LMERs will be utilized for each primary endpoint (aggregated averages of momentary negative affect), with a primary LMER estimating the difference between Baseline and Week 1. The Time x Group interaction will be the primary focus of interest, and we aim to evaluate 1) the extent to which the primary endpoint differs between Baseline and Week 1, and 2) the extent to which that difference varies between the Psilocybin and Control groups.

Changes in Pain Catastrophizing as assessed by the Pain Catastrophizing Scale and averaged over 7-day periods of Ecological Momentary Assessment (EMA)

Pain catastrophizing will be assessed with three items taken from the Pain Catastrophizing Scale that have been specifically validated for use in Ecological Momentary Assessment (EMA) studies of patients with chronic pain. Items will be administered via EMA and scores will be aggregated over 7-day EMA periods at baseline, post-session, and 1-month follow-up. Each item is on a 5-point Likert scale (ranging from 0, "Not at all", to 4, "All the time"). Higher scores on each of these items indicates increased pain catastrophizing. A separate set of LMERs will be utilized for each primary endpoint (aggregated averages of momentary pain catastrophizing), with a primary LMER estimating the difference between Baseline and Week 1. The Time x Group interaction will be the primary focus of interest, and we aim to evaluate 1) the extent to which the primary endpoint differs between Baseline and Week 1, and 2) the extent to which that difference varies between the Psilocybin and Control groups.

Changes in Positive Affective Pain Inhibition (Quantitative Sensory Testing)

Positive Affective Pain Inhibition will be assessed using quantitative sensory testing at baseline, 1-week post-drug-administration, and 1-month post-drug-administration. Positive affective pain inhibition is measured as the difference in pain ratings to noxious stimuli administered during the presentation of positive/rewarding stimuli relative to neutral or negative stimuli. A separate set of LMERs will be utilized for each primary endpoint (index of Positive Affective Pain Inhibition), with a primary LMER estimating the difference between Baseline and Week 1. The Time x Group interaction will be the primary focus of interest, and we aim to evaluate 1) the extent to which the primary endpoint differs between Baseline and Week 1, and 2) the extent to which that difference varies between the Psilocybin and Control groups.

Changes in positive affect as assessed by discrete positive affect items and averaged over 7-day periods of Ecological Momentary Assessment (EMA)

Discrete positive affect items: joy, love, hope, contentment. Positive affect will be assessed by asking participants to rate the intensity of four discrete positive emotions (joy, love, hope, contentment) on a 5-point Likert scale from 1-5 ("Very slightly or not at all" to "Extremely") and averaging discrete items. Positive Affect scores will be aggregated over 7-day EMA periods at baseline, post-session, and 1-month follow-up. Higher Positive Affect scores represent higher levels of positive affect. A separate set of LMERs will be utilized for each endpoint (aggregated averages of momentary positive affect), with a secondary LMER estimating the difference between Baseline and 1-Month. The Time x Group interaction will be the primary focus of interest, and we aim to evaluate 1) the extent to which the secondary endpoint differs between Baseline and 1-Month, and 2) the extent to which that difference varies between the Psilocybin and Control groups.

Changes in negative affect as assessed by discrete negative affect items and averaged over 7-day periods of Ecological Momentary Assessment (EMA)

Discrete negative emotion items: depressed, angry, frustrated, and worried. Negative affect will be assessed by asking participants to rate the intensity of four discrete negative emotions (depressed, angry, frustrated, and worried) on a 5-point Likert scale from 1-5 ("Very slightly or not at all" to "Extremely") and averaging discrete items. Negative Affect scores will be aggregated over 7-day EMA periods at baseline, post-session, and 1-month follow-up. Lower Negative Affect scores represent lower levels of negative affect. A separate set of LMERs will be utilized for each endpoint (aggregated averages of momentary negative affect), with a secondary LMER estimating the difference between Baseline and 1-Month. The Time x Group interaction will be the primary focus of interest, and we aim to evaluate 1) the extent to which the secondary endpoint differs between Baseline and 1-Month, and 2) the extent to which that difference varies between the Psilocybin and Control groups.

Changes in Pain Catastrophizing as assessed by the Pain Catastrophizing Scale and averaged over 7-day periods of Ecological Momentary Assessment (EMA)

Pain catastrophizing will be assessed with three items taken from the Pain Catastrophizing Scale that have been specifically validated for use in Ecological Momentary Assessment (EMA) studies of patients with chronic pain. Items will be administered via EMA and scores will be aggregated over 7-day EMA periods at baseline, post-session, and 1-month follow-up. Each item is on a 5-point Likert scale (ranging from 0, "Not at all", to 4, "All the time"). Higher scores on each of these items indicates increased pain catastrophizing. A separate set of LMERs will be utilized for each endpoint (aggregated averages of momentary pain catastrophizing), with a secondary LMER estimating the difference between Baseline and 1-Month. The Time x Group interaction will be the primary focus of interest, and we aim to evaluate 1) the extent to which the secondary endpoint differs between Baseline and 1-Month, and 2) the extent to which that difference varies between the Psilocybin and Control groups.

Changes in Positive Affective Pain Inhibition (Quantitative Sensory Testing)

Positive Affective Pain Inhibition will be assessed using quantitative sensory testing at baseline, 1-week post-drug-administration, and 1-month post-drug-administration. Positive affective pain inhibition is measured as the difference in pain ratings to noxious stimuli administered during the presentation of positive/rewarding stimuli relative to neutral or negative stimuli. A separate set of LMERs will be utilized for each endpoint (index of Positive Affective Pain Inhibition), with a secondary LMER estimating the difference between Baseline and 1-Month. The Time x Group interaction will be the primary focus of interest, and we aim to evaluate 1) the extent to which the secondary endpoint differs between Baseline and 1-Month, and 2) the extent to which that difference varies between the Psilocybin and Control groups.

Pain as assessed by discrete pain items assessed via EMA

Discrete pain items include 'Rate your current level of pain' and 'Over the past hour: Rate the worst pain you experienced.' These items will be assessed multiple times daily during each EMA items. These items will be averaged over each EMA burst to determine pain levels over the course of trial participant. A separate set of LMERs will be utilized for each endpoint (aggregated averages of momentary pain ratings), with LMERs estimating the differences between Baseline and 1-Week as well as 1-Month. The Time x Group interaction will be the primary focus of interest, and we aim to evaluate 1) the extent to which the endpoint differs between Baseline and 1-Week as well as 1-Month, and 2) the extent to which that difference varies between the Psilocybin and Control groups.

Dynamic association between affect and pain using micro-longitudinal EMA data of affective variables (positive, negative affect outcomes) and pain outcomes

Our secondary analytic strategy will focus on the dynamic association between affect and pain using the micro-longitudinal EMA data, in which the EMA data is organized hierarchically with Waves (Baseline, 1-week, 1-month) nested within People, Days nested within Waves, and Momentary Observations (up to four) nested within Days. For each EMA wave (Baseline, 1-week, and 1-month), we will utilize separate LMERs to evaluate the momentary (i) concurrent and (ii) lagged associations between affective variables and pain. In each LMER, person-mean centered day-level affective variables and Group (Psilocybin vs. Methylphenidate) will be included as fixed effects; day-level intercept and participant-level intercept will be included as random effects. Results from these LMERs will also allow us to evaluate the extent to which the momentary concurrent/lagged associations differ by group at each EMA wave.

Changes in mood as measured by a selection of discrete items derived from the Positive and Negative Affect Schedule- Expanded Form (PANAS-X).

The selected, discrete positive and negative affect items described in Primary Outcome 1 will be supplemented by a selection of discrete items derived from the Positive and Negative Affect Schedule- Expanded Form (PANAS-X) and measured via Ecological Momentary Assessment (EMA).

Changes in self-reported Pain Impact as measured by Pain intensity (P), interference with Enjoyment of life (E), and interference with General activity (G) Scale (PEG)

Pain impact will be assessed with the Pain average, interference with Enjoyment of life, and interference with General activity (PEG), which will be assessed with EMA over the course of three distinct 7-day periods at baseline, immediately following drug session, and leading up to 1-month follow-up to permit time-varying analyses of the associations of affective mechanisms with pain and function. The PEG is a three-item measure scored, with each item rated on a scale of 0-10. Higher scores indicate higher levels of pain intensity or higher levels of interference of interference with enjoyment/general activity, depending on the item. Overall, higher scores indicate higher levels of pain impact.