Psilocybin in Chronic Low Back Pain and Depression

NCT06355414 | Recruiting Phase 1 FDA Drug

• 2 other identifiers: IRB00385932R33AT012317
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

This study seeks to provide insight on psilocybin's effects on mechanisms of chronic pain among patients with co-morbid chronic low back pain and depression (CLBP+D). Participants will receive either a single high-dose of psilocybin (25mg absolute dose) or methylphenidate (40mg absolute dose). Participants will be asked to complete assessments of pain, depressive symptoms, and more general questionnaires regarding the participants experiences during the experimental sessions and the associated enduring effects.

Conditions

Chronic Low-back Pain; Depression

Keywords

Psilocybin; Chronic Low-back Pain; Depression

Outcome Measures

Primary Outcomes (4)

• 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.

  7-day period of EMA Post-drug Session (1-day through 1-week after drug session) relative to Baseline (beginning the day after baseline visit is complete)

• 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.

  7-day period of EMA Post-drug Session (1-day through 1-week after drug session) relative to Baseline (beginning the day after baseline visit is complete)

• 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.

  7-day period of EMA Post-drug Session (1-day through 1-week after drug session) relative to Baseline (beginning the day after baseline visit is complete)

• 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.

  Baseline, 1-week follow-up

Secondary Outcomes (4)

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

  7-day period of EMA 1-month Post-drug (7 days leading up to 1-month follow-up) relative to Baseline (beginning the day after baseline visit is complete)

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

  7-day period of EMA 1-month Post-drug (7 days leading up to 1-month follow-up) relative to Baseline (beginning the day after baseline visit is complete)

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

  7-day period of EMA 1-month Post-drug (7 days leading up to 1-month follow-up) relative to Baseline (beginning the day after baseline visit is complete)

• Changes in Positive Affective Pain Inhibition (Quantitative Sensory Testing)

  Baseline, 1-Month follow-up

Other Outcomes (21)

• Pain as assessed by discrete pain items assessed via EMA

  7-day periods of EMA at 1-week follow-up and 1-month follow-up, each relative to Baseline

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

  7-day periods of EMA at: Baseline (beginning the day after baseline visit is complete), Post-drug Session (beginning the day after drug session), and 1-month follow-up (the seven days leading up to the 1-month follow-up visit)

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

  7-day periods of EMA at: Baseline (beginning the day after baseline visit is complete), Post-drug Session (beginning the day after drug session), and 1-month follow-up (the seven days leading up to the 1-month follow-up visit)

Study Arms (2)

Psilocybin

EXPERIMENTAL

This arm will receive a single, absolute dose (25 mg) of psilocybin.

Drug: Psilocybin

Methylphenidate

ACTIVE COMPARATOR

This arm will receive a single, absolute dose (40 mg) of methylphenidate.

Drug: Methylphenidate

Interventions

Psilocybin DRUG

Drug administration under supportive conditions

Psilocybin

Methylphenidate DRUG

Drug administration under supportive conditions

Methylphenidate

Eligibility Criteria

• Age: 21 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• to 80 years old
• Have given written informed consent
• Report low back pain as ongoing problem ≥ 3 months and any low back pain on at least half of the days over the past 6 months (consistent with NIH Consensus Recommendations for defining CLBP; other chronic pain problems can be present, but CLBP must be reported as primary)
• Report at least moderate depression symptoms Grid-Hamilton Depression Rating Scale (GRID-HAMD) ≥ 17
• Fluent in English
• At least high school level of education
• Agree to abstain from any psychoactive drugs on the day prior to and the day of the drug administration session
• Women who are of childbearing potential and sexually active who are not practicing an effective means of birth control must agree to practice an effective means of birth control throughout the duration of the study
• Be judged by study team clinicians to be at low risk for suicidality
• Concurrent psychotherapy or pharmacotherapy with selective serotonin reuptake inhibitors (SSRIs), serotonin and norephinephrine reuptake inhibitors (SNRIs), and/or bupropion (\< 300 mg bupropion) is allowed if the type and frequency of the therapy has been stable for at least two months prior to screening and is expected to remain stable during participation in the study.
• Concurrent psychotherapy is allowed if the type and frequency of the therapy has been stable for at least two months prior to screening and is expected to remain stable during participation in the study
• Be otherwise medically stable as determined by screening for medical problems via a personal interview, a medical questionnaire, a physical examination, an electrocardiogram (ECG), and routine medical blood and urinalysis laboratory tests; CBC, comprehensive metabolic panel (CMP), urine beta-human chorionic gonadotropin (HCG), urine toxicology screen.
• Agree to consume approximately the same amount of caffeine-containing beverage (e.g., coffee, tea) that he/she consumes on a usual morning, before arriving at the research unit on the mornings of drug session days. If the participant does not routinely consume caffeinated beverages, he/she must agree not to do so on session days.
• Agree not to take any as needed (PRN) medications on the mornings of drug sessions
• Agree not to take sildenafil (Viagra®), tadalafil, or similar medications within 72 hours of each drug administration

You may not qualify if:

• Lifetime history of serious psychiatric (other than depression) or neurological disorders, including bipolar disorder, psychosis, or seizure disorder
• History (past 2 years) of severe substance use disorder or current (past six months) substance use disorder of moderate severity
• Clinically significant suicidal ideation (e.g. with strong intent or means) within past 6 months or history (past 5 years) of suicide attempt
• Medical condition incompatible with psilocybin administration (e.g., cardiovascular)
• On unstable/changing dose of opioid, benzodiazepine or other psychoactive or pain medication within 4 weeks prior to enrollment and/or unable to abstain from medication on drug administration day
• Current use/positive toxicology for illicit drugs or positive breath alcohol test at screening and prior to each drug administration session.
• Clinically significant transaminitis- aspertate aminotransferase (AST) or alanine aminotransferase (ALT) greater than two times normal value).
• Women who are pregnant (as indicated by a positive urine pregnancy test assessed at intake and before each drug session) or nursing;
• Women who are of childbearing potential and sexually active who are not practicing an effective means of birth control.
• Cardiovascular conditions: coronary artery disease, stroke, angina, uncontrolled hypertension, a clinically significant ECG abnormality (e.g., atrial fibrillation), prolonged corrected QT interval (QTc) interval (i.e., QTc \> 450 msec), heart valve, or transient ischemic attack (TIA) in the past year.
• History of seizures and/or epilepsy with history of seizures.
• Type 1 diabetes.
• BMI \< 18
• Medical conditions contraindicated for methylphenidate administration:
• Concomitant use of Monoamine oxidase inhibitors (MAOIs), or use within 14 days of MAOI discontinuation

Sponsors & Collaborators

• Johns Hopkins University: lead
• National Center for Complementary and Integrative Health (NCCIH): collaborator

Study Sites (1)

Johns Hopkins University School of Medicine

Baltimore, Maryland, 21224, United States

RECRUITING

Related Publications (28)

• Mak HW, Schneider S. Individual differences in momentary pain-affect coupling and their associations with mental health in patients with chronic pain. J Psychosom Res. 2020 Nov;138:110227. doi: 10.1016/j.jpsychores.2020.110227. Epub 2020 Aug 28.

  PMID: 32919151 BACKGROUND

• Roy M, Peretz I, Rainville P. Emotional valence contributes to music-induced analgesia. Pain. 2008 Jan;134(1-2):140-7. doi: 10.1016/j.pain.2007.04.003. Epub 2007 May 25.

  PMID: 17532141 BACKGROUND

• Sullivan MJ, Bishop SR, & Pivik J (1995). The pain catastrophizing scale: development and validation. Psychol Assess, 7(4): 524.

  BACKGROUND

• Vanderlind WM, Everaert J, Joormann J. Positive emotion in daily life: Emotion regulation and depression. Emotion. 2022 Oct;22(7):1614-1624. doi: 10.1037/emo0000944. Epub 2021 Mar 4.

  PMID: 33661667 BACKGROUND

• Yaden, D. B., Kaufman, S. B., Hyde, E., Chirico, A., Gaggioli, A., Zhang, J. W., & Keltner, D. (2019). The development of the Awe Experience Scale (AWE-S): A multifactorial measure for a complex emotion. The Journal of Positive Psychology, 14(4): 474-488.

  BACKGROUND

• Kroenke K, Wu J, Bair MJ, Krebs EE, Damush TM, Tu W. Reciprocal relationship between pain and depression: a 12-month longitudinal analysis in primary care. J Pain. 2011 Sep;12(9):964-73. doi: 10.1016/j.jpain.2011.03.003. Epub 2011 Jun 16.

  PMID: 21680251 BACKGROUND

• Krebs EE, Lorenz KA, Bair MJ, Damush TM, Wu J, Sutherland JM, Asch SM, Kroenke K. Development and initial validation of the PEG, a three-item scale assessing pain intensity and interference. J Gen Intern Med. 2009 Jun;24(6):733-8. doi: 10.1007/s11606-009-0981-1. Epub 2009 May 6.

  PMID: 19418100 BACKGROUND

• Griffiths RR, Johnson MW, Carducci MA, Umbricht A, Richards WA, Richards BD, Cosimano MP, Klinedinst MA. Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial. J Psychopharmacol. 2016 Dec;30(12):1181-1197. doi: 10.1177/0269881116675513.

  PMID: 27909165 BACKGROUND

• Griffiths RR, Richards WA, McCann U, Jesse R. Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance. Psychopharmacology (Berl). 2006 Aug;187(3):268-83; discussion 284-92. doi: 10.1007/s00213-006-0457-5. Epub 2006 Jul 7.

  PMID: 16826400 BACKGROUND

• Gratz, K. L., & Roemer, L. (2004). Multidimensional Assessment of Emotion Regulation and Dysregulation: Development, Factor Structure, and Initial Validation of the Difficulties in Emotion Regulation Scale. Journal of Psychopathology & Behavioral Assessment, 26(1): 41

  BACKGROUND

• George SZ, Calley D, Valencia C, Beneciuk JM. Clinical Investigation of Pain-related Fear and Pain Catastrophizing for Patients With Low Back Pain. Clin J Pain. 2011 Feb;27(2):108-15. doi: 10.1097/AJP.0b013e3181f21414.

  PMID: 20842009 BACKGROUND

• Freynhagen R, Baron R, Gockel U, Tolle TR. painDETECT: a new screening questionnaire to identify neuropathic components in patients with back pain. Curr Med Res Opin. 2006 Oct;22(10):1911-20. doi: 10.1185/030079906X132488.

  PMID: 17022849 BACKGROUND

• Flink IL, Boersma K, Linton SJ. Pain catastrophizing as repetitive negative thinking: a development of the conceptualization. Cogn Behav Ther. 2013;42(3):215-23. doi: 10.1080/16506073.2013.769621.

  PMID: 23978106 BACKGROUND

• Finan PH, Garland EL. The role of positive affect in pain and its treatment. Clin J Pain. 2015 Feb;31(2):177-87. doi: 10.1097/AJP.0000000000000092.

  PMID: 24751543 BACKGROUND

• Fairbank JC, Pynsent PB. The Oswestry Disability Index. Spine (Phila Pa 1976). 2000 Nov 15;25(22):2940-52; discussion 2952. doi: 10.1097/00007632-200011150-00017.

  PMID: 11074683 BACKGROUND

• Dittrich A. The standardized psychometric assessment of altered states of consciousness (ASCs) in humans. Pharmacopsychiatry. 1998 Jul;31 Suppl 2:80-4. doi: 10.1055/s-2007-979351.

  PMID: 9754838 BACKGROUND

• Davis AK, Barrett FS, So S, Gukasyan N, Swift TC, Griffiths RR. Development of the Psychological Insight Questionnaire among a sample of people who have consumed psilocybin or LSD. J Psychopharmacol. 2021 Apr;35(4):437-446. doi: 10.1177/0269881120967878. Epub 2021 Jan 9.

  PMID: 33427007 BACKGROUND

• Barrett FS, Johnson MW, Griffiths RR. Validation of the revised Mystical Experience Questionnaire in experimental sessions with psilocybin. J Psychopharmacol. 2015 Nov;29(11):1182-90. doi: 10.1177/0269881115609019. Epub 2015 Oct 6.

  PMID: 26442957 BACKGROUND

• Barrett FS, Bradstreet MP, Leoutsakos JS, Johnson MW, Griffiths RR. The Challenging Experience Questionnaire: Characterization of challenging experiences with psilocybin mushrooms. J Psychopharmacol. 2016 Dec;30(12):1279-1295. doi: 10.1177/0269881116678781. Epub 2016 Nov 17.

  PMID: 27856683 BACKGROUND

• McCracken LM, Yang SY. The role of values in a contextual cognitive-behavioral approach to chronic pain. Pain. 2006 Jul;123(1-2):137-45. doi: 10.1016/j.pain.2006.02.021. Epub 2006 Mar 29.

  PMID: 16564627 BACKGROUND

• Hays RD, Spritzer KL, Schalet BD, Cella D. PROMIS(R)-29 v2.0 profile physical and mental health summary scores. Qual Life Res. 2018 Jul;27(7):1885-1891. doi: 10.1007/s11136-018-1842-3. Epub 2018 Mar 22.

  PMID: 29569016 BACKGROUND

• Clifton JDW, Yaden DB. Brief measures of the four highest-order primal world beliefs. Psychol Assess. 2021 Dec;33(12):1267-1273. doi: 10.1037/pas0001055. Epub 2021 Jul 1.

  PMID: 34197163 BACKGROUND

• Baer RA, Smith GT, Hopkins J, Krietemeyer J, Toney L. Using self-report assessment methods to explore facets of mindfulness. Assessment. 2006 Mar;13(1):27-45. doi: 10.1177/1073191105283504.

  PMID: 16443717 BACKGROUND

• Nakonezny PA, Carmody TJ, Morris DW, Kurian BT, Trivedi MH. Psychometric evaluation of the Snaith-Hamilton pleasure scale in adult outpatients with major depressive disorder. Int Clin Psychopharmacol. 2010 Nov;25(6):328-33. doi: 10.1097/YIC.0b013e32833eb5ee.

  PMID: 20805756 BACKGROUND

• Shiota, M. N., Keltner, D., & John, O. P. (2006). Positive emotion dispositions differentially associated with Big Five personality and attachment style. The Journal of Positive Psychology, 1(2), 61-71. DOI: 10.1080/17439760500510833

  BACKGROUND

• Von Korff M, DeBar LL, Krebs EE, Kerns RD, Deyo RA, Keefe FJ. Graded chronic pain scale revised: mild, bothersome, and high-impact chronic pain. Pain. 2020 Mar;161(3):651-661. doi: 10.1097/j.pain.0000000000001758.

  PMID: 31764390 BACKGROUND

• Wicksell RK, Lekander M, Sorjonen K, Olsson GL. The Psychological Inflexibility in Pain Scale (PIPS)--statistical properties and model fit of an instrument to assess change processes in pain related disability. Eur J Pain. 2010 Aug;14(7):771.e1-14. doi: 10.1016/j.ejpain.2009.11.015. Epub 2010 Jan 27.

  PMID: 20106685 BACKGROUND

• Yarnitsky D, Bouhassira D, Drewes AM, Fillingim RB, Granot M, Hansson P, Landau R, Marchand S, Matre D, Nilsen KB, Stubhaug A, Treede RD, Wilder-Smith OH. Recommendations on practice of conditioned pain modulation (CPM) testing. Eur J Pain. 2015 Jul;19(6):805-6. doi: 10.1002/ejp.605. Epub 2014 Oct 20.

  PMID: 25330039 BACKGROUND

MeSH Terms

Conditions

Depression

Interventions

Psilocybin; Methylphenidate

Condition Hierarchy (Ancestors)

Behavioral Symptoms; Behavior

Intervention Hierarchy (Ancestors)

Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Tryptamines; Indolizidines; Indolizines; Phenylacetates; Acids, Carbocyclic; Carboxylic Acids; Organic Chemicals; Piperidines; Heterocyclic Compounds, 1-Ring

Study Officials

• David B Yaden, PhD

  Johns Hopkins University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Arozo Azimi, BA

CONTACT

410-550-1140; LowBackPain@jh.edu

Kelcy A Klein, BS

CONTACT

410-550-1140; LowBackPain@jh.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: This is a double-blind trial, and efforts will be made to mask the study drug (psilocybin) and the active control (methylphenidate) from participants, guides, and study staff. Participants will be debriefed about their randomly assigned drug condition after the completion of the final follow-up assessment, or after discontinuation/withdrawal, whichever comes first.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Randomized, double-blind, active control study comparing the effects of psilocybin (25mg fixed dose) and methylphenidate (40mg fixed dose)

Study Record Dates

• First Submitted: March 26, 2024
• First Posted: April 9, 2024
• Study Start: April 22, 2024
• Primary Completion (Estimated): July 30, 2026
• Study Completion (Estimated): August 30, 2026
• Last Updated: October 14, 2025

Record last verified: 2025-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)