MDMA-assisted psychotherapy for treatment of anxiety and other psychological distress related to life-threatening illnesses: a randomized pilot study

Philip E Wolfson, Julane Andries, Allison A Feduccia, Lisa Jerome, Julie B Wang, Emily Williams, Shannon C Carlin, Evan Sola, Scott Hamilton, Berra Yazar-Klosinski, Amy Emerson, Michael C Mithoefer, Rick Doblin, Philip E Wolfson, Julane Andries, Allison A Feduccia, Lisa Jerome, Julie B Wang, Emily Williams, Shannon C Carlin, Evan Sola, Scott Hamilton, Berra Yazar-Klosinski, Amy Emerson, Michael C Mithoefer, Rick Doblin

Abstract

The success of modern medicine creates a growing population of those suffering from life-threatening illnesses (LTI) who often experience anxiety, depression, and existential distress. We present a novel approach; investigating MDMA-assisted psychotherapy for the treatment of anxiety in people with an LTI. Participants with anxiety from an LTI were randomized in a double-blind study to receive MDMA (125 mg, n = 13) or placebo (n = 5) in combination with two 8-h psychotherapy sessions. The primary outcome was change in State-Trait Anxiety Inventory (STAI) Trait scores from baseline to one month post the second experimental session. After unblinding, participants in the MDMA group had one open-label MDMA session and placebo participants crossed over to receive three open-label MDMA sessions. Additional follow-up assessments occurred six and twelve months after a participant's last experimental session. At the primary endpoint, the MDMA group had a greater mean (SD) reduction in STAI-Trait scores, - 23.5 (13.2), indicating less anxiety, compared to placebo group, - 8.8 (14.7); results did not reach a significant group difference (p = .056). Hedges' g between-group effect size was 1.03 (95% CI: - 5.25, 7.31). Overall, MDMA was well-tolerated in this sample. These preliminary findings can inform development of larger clinical trials to further examine MDMA-assisted psychotherapy as a novel approach to treat individuals with LTI-related anxiety.Trial Registration: clinicaltrials.gov Identifier: NCT02427568, first registered April 28, 2015.

Conflict of interest statement

Philip Wolfson received contractual support from MAPS to serve as the study’s principal investigator. Julane Andries received compensation for her work as a therapist in the study from MAPS. Allison Feduccia received salary support for full time employment with MAPS Public Benefit Corporation. Lisa Jerome received salary support for full time employment with MAPS Public Benefit Corporation. Julie Wang received salary support for full time employment with MAPS Public Benefit Corporation. Emily Williams received compensation for her work as an independent rater in the study from MAPS. Shannon Carlin received compensation for her work as a therapist in the study from MAPS. Evan Sola received compensation for his work as a therapist in the study from MAPS. Scott Hamilton received research funds from MAPS Public Benefit Corporation for his role as a biostatistician. Berra Yazar-Klosinski received salary support for full time employment with MAPS. Amy Emerson received salary support for full time employment with MAPS Public Benefit Corporation. Michael Mithoefer received compensation for his work as medical monitor. Rick Doblin received salary support for full time employment with MAPS.

Figures

Figure 1
Figure 1
CONSORT diagram.
Figure 2
Figure 2
Mean (SD) STAI Trait scores for MDMA and Placebo groups at baseline and post treatment. Mean (SD) State Trait Anxiety Inventory scores across time at baseline, primary endpoint (one-month post second blinded experimental session), end of stage 1 (one month post third MDMA session, i.e. treatment exit for MDMA 125 mg group), secondary endpoint (one month post second open-label session), end of stage 2 (one month post third open-label session, i.e. treatment exit for control group), 6-month follow-up, and 12-month follow-up. The grey box represents the open-label crossover after placebo group was unblinded at the primary endpoint. Groups were collapsed for long-term follow-ups since all participants had received active doses of MDMA in either the blinded or open-label stage
Figure 3
Figure 3
Study design.

References

    1. Grunfeld E, et al. Family caregiver burden: results of a longitudinal study of breast cancer patients and their principal caregivers. CMAJ. 2004;170:1795–1801. doi: 10.1503/cmaj.1031205.
    1. Jacobsen PB, et al. Posttraumatic stress disorder symptoms after bone marrow transplantation for breast cancer. Psychosom. Med. 1998;60:366–371. doi: 10.1097/00006842-199805000-00026.
    1. Grassi L, Costantini A. Psychosocial needs and well-being issues of long-term survivors and cured cancer patients. Epidemiol. Prev. 2014;38:126–129.
    1. Iconomou G, et al. Emotional distress in cancer patients at the beginning of chemotherapy and its relation to quality of life. J. BUON. 2008;13:217–222.
    1. Wolfson, P. Noe: A Fafther-Son Song of Love, Life, Illness and Death. (North Atlantic Books, 2011).
    1. Kast E, Collins V. Study of lysergic acid diethylamide as an analgesic agent. Anesth. Analg. 1964;43:285–291. doi: 10.1213/00000539-196405000-00013.
    1. Kurland, A. A., Grof, S., Pahnke, W. N. & Goodman, L. E. In Psychotheramacological Agents for the Terminally Ill and Bereaved. (eds Goldberger, I. K. et al.) 86–133 (Columbia University Press, 1973).
    1. Gasser P, et al. Safety and efficacy of lysergic acid diethylamide-assisted psychotherapy for anxiety associated with life-threatening diseases. J. Nerv. Ment. Dis. 2014;202:513–520. doi: 10.1097/NMD.0000000000000113.
    1. Griffiths RR, et al. Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: a randomized double-blind trial. J. Psychopharmacol. 2016;30:1181–1197. doi: 10.1177/0269881116675513.
    1. Grob, C. S., Bossis, A. P. & Griffiths, R. R. In Psychological Aspects of Cancer 291–308 (Springer, 2013).
    1. Ross S, et al. Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial. J. Psychopharmacol. 2016;30:1165–1180. doi: 10.1177/0269881116675512.
    1. Grob CS, et al. Pilot study of psilocybin treatment for anxiety in patients with advanced-stage cancer. Arch. Gen. Psychiatry. 2011;68:71–78. doi: 10.1001/archgenpsychiatry.2010.116.
    1. Blinderman CD. Psycho-existential distress in cancer patients: a return to "entheogens". J. Psychopharmacol. 2016;30:1205–1206. doi: 10.1177/0269881116675761.
    1. Mithoefer MC, Grob CS, Brewerton TD. Novel psychopharmacological therapies for psychiatric disorders: psilocybin and MDMA. The lancet. Psychiatry. 2016 doi: 10.1016/S2215-0366(15)00576-3.
    1. Griffiths R, Richards W, Johnson M, McCann U, Jesse R. Mystical-type experiences occasioned by psilocybin mediate the attribution of personal meaning and spiritual significance 14 months later. J. Psychopharmacol. 2008;22:621–632. doi: 10.1177/0269881108094300.
    1. Feduccia AA, Holland J, Mithoefer MC. Progress and promise for the MDMA drug development program. Psychopharmacology. 2018;235:561–571. doi: 10.1007/s00213-017-4779-2.
    1. Mithoefer MC, et al. 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for post-traumatic stress disorder in military veterans, firefighters, and police officers: a randomised, double-blind, dose-response, phase 2 clinical trial. Lancet Psychiatry. 2018;5:486–497. doi: 10.1016/s2215-0366(18)30135-4.
    1. Mithoefer MC, Wagner MT, Mithoefer AT, Jerome L, Doblin R. The safety and efficacy of {+/-}3,4-methylenedioxymethamphetamine-assisted psychotherapy in subjects with chronic, treatment-resistant posttraumatic stress disorder: the first randomized controlled pilot study. J. Psychopharmacol. 2011;25:439–452. doi: 10.1177/0269881110378371.
    1. Mithoefer MC, et al. Durability of improvement in post-traumatic stress disorder symptoms and absence of harmful effects or drug dependency after 3,4-methylenedioxymethamphetamine-assisted psychotherapy: a prospective long-term follow-up study. J. Psychopharmacol. 2013;27:28–39. doi: 10.1177/0269881112456611.
    1. Oehen P, Traber R, Widmer V, Schnyder U. A randomized, controlled pilot study of MDMA (+/- 3,4-Methylenedioxymethamphetamine)-assisted psychotherapy for treatment of resistant, chronic post-traumatic stress disorder (PTSD) J. Psychopharmacol. 2013;27:40–52. doi: 10.1177/0269881112464827.
    1. Ot'alora GM, et al. 3,4-Methylenedioxymethamphetamine-assisted psychotherapy for treatment of chronic posttraumatic stress disorder: a randomized phase 2 controlled trial. J. Psychopharmacol. 2018;32:1295–1307. doi: 10.1177/0269881118806297.
    1. Danforth AL, et al. Reduction in social anxiety after MDMA-assisted psychotherapy with autistic adults: a randomized, double-blind, placebo-controlled pilot study. Psychopharmacology. 2018 doi: 10.1007/s00213-018-5010-9.
    1. Carhart-Harris RL, et al. The effects of acutely administered 3,4-methylenedioxymethamphetamine on spontaneous brain function in healthy volunteers measured with arterial spin labeling and blood oxygen level-dependent resting state functional connectivity. Biol. Psychiatry. 2015;78:554–562. doi: 10.1016/j.biopsych.2013.12.015.
    1. Kamilar-Britt P, Bedi G. The prosocial effects of 3,4-methylenedioxymethamphetamine (MDMA): controlled studies in humans and laboratory animals. Neurosci. Biobehav. Rev. 2015;57:433–446. doi: 10.1016/j.neubiorev.2015.08.016.
    1. Walpola IC, et al. Altered insula connectivity under MDMA. Neuropsychopharmacology. 2017;42:2152–2162. doi: 10.1038/npp.2017.35.
    1. Bedi G, Phan KL, Angstadt M, de Wit H. Effects of MDMA on sociability and neural response to social threat and social reward. Psychopharmacology. 2009;207:73–83. doi: 10.1007/s00213-009-1635-z.
    1. Feduccia AA, Mithoefer MC. MDMA-assisted psychotherapy for PTSD: are memory reconsolidation and fear extinction underlying mechanisms? Prog. Neuropsychopharmacol. Biol. Psychiatry. 2018;84:221–228. doi: 10.1016/j.pnpbp.2018.03.003.
    1. Kamboj SK, et al. Additive effects of 3,4-methylenedioxymethamphetamine (MDMA) and compassionate imagery on self-compassion in recreational users of ecstasy. Mindfulness (N Y) 2018;9:1134–1145. doi: 10.1007/s12671-017-0849-0.
    1. Young MB, Andero R, Ressler KJ, Howell LL. 3,4-Methylenedioxymethamphetamine facilitates fear extinction learning. Transl. Psychiatry. 2015;5:e634. doi: 10.1038/tp.2015.138.
    1. Young MB, et al. Inhibition of serotonin transporters disrupts the enhancement of fear memory extinction by 3,4-methylenedioxymethamphetamine (MDMA) Psychopharmacology. 2017 doi: 10.1007/s00213-017-4684-8.
    1. Allen J, et al. Posttraumatic stress-related psychological functioning in adult survivors of childhood cancer. J. Cancer Surviv. 2018;12:216–223. doi: 10.1007/s11764-017-0660-x.
    1. Goldfinger JZ, et al. Correlates of post-traumatic stress disorder in stroke survivors. J. Stroke Cerebrovasc. Dis. 2014;23:1099–1105. doi: 10.1016/j.jstrokecerebrovasdis.2013.09.019.
    1. Oflaz S, et al. Does illness perception predict posttraumatic stress disorder in patients with myocardial infarction? Noro Psikiyatr Ars. 2014;51:103–109. doi: 10.4274/npa.y6394.
    1. First, M. B., Spitzer, R. L., Gibbon. M. & Williams, J. B. W. Structured Clinical Interview for DSM-IV Axis I Disorders - Patient Edition (SCID-I/P, Version 2.0, 4/97 Revision). (Biometrics Research Department, New York State Psychiatric Institute, 1997).
    1. Spielberger, C. D., Gorsuch, R. L., Lushene, R. E., Vagg, P. R. & Jacobs, G. A. Manual for the State-Trait Anxiety Inventory. (Consulting Psychologists Press, 1983).
    1. Tedeschi RG, Calhoun LG. The posttraumatic growth inventory: measuring the positive legacy of trauma. J. Trauma. Stress. 1996;9:455–471. doi: 10.1002/jts.2490090305.
    1. Baer RA, Smith GT, Hopkins J, Krietemeyer J, Toney L. Using self-report assessment methods to explore facets of mindfulness. Assessment. 2006;13:27–45. doi: 10.1177/1073191105283504.
    1. Baer RA, et al. Construct validity of the five facet mindfulness questionnaire in meditating and nonmeditating samples. Assessment. 2008;15:329–342. doi: 10.1177/1073191107313003.
    1. Beck AT, Steer RA. Internal consistencies of the original and revised beck depression inventory. J. Clin. Psychol. 1984;40:1365–1367. doi: 10.1002/1097-4679(198411)40:6<1365::AID-JCLP2270400615>;2-D.
    1. Beck AT, Steer RA, Ball R, Ranieri W. Comparison of beck depression inventories -IA and -II in psychiatric outpatients. J. Pers. Assess. 1996;67:588–597. doi: 10.1207/s15327752jpa6703_13.
    1. Buysse DJ, Reynolds CF, 3rd, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh sleep quality index: a new instrument for psychiatric practice and research. Psychiatry Res. 1989;28:193–213. doi: 10.1016/0165-1781(89)90047-4.
    1. Cella D, Eton DT, Lai JS, Peterman AH, Merkel DE. Combining anchor and distribution-based methods to derive minimal clinically important differences on the Functional Assessment of Cancer Therapy (FACT) anemia and fatigue scales. J. Pain Symptom Manag. 2002;24:547–561. doi: 10.1016/S0885-3924(02)00529-8.
    1. Cella D, Nowinski CJ. Measuring quality of life in chronic illness: the functional assessment of chronic illness therapy measurement system. Arch. Phys. Med. Rehabil. 2002;83:S10–17. doi: 10.1053/apmr.2002.36959.
    1. Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br. J. Psychiatry. 1979;134:382–389. doi: 10.1192/bjp.134.4.382.
    1. Andrykowski MA, Cordova MJ, Studts JL, Miller TW. Posttraumatic stress disorder after treatment for breast cancer: prevalence of diagnosis and use of the PTSD Checklist-Civilian Version (PCL-C) as a screening instrument. J. Consult. Clin. Psychol. 1998;66:586–590. doi: 10.1037/0022-006X.66.3.586.
    1. Cordova MJ, et al. Frequency and correlates of posttraumatic-stress-disorder-like symptoms after treatment for breast cancer. J. Consult. Clin. Psychol. 1995;63:981–986. doi: 10.1037/0022-006X.63.6.981.
    1. Greer G, Tolbert R. Subjective reports of the effects of MDMA in a clinical setting. J. Psychoactive Drugs. 1986;18:319–327. doi: 10.1080/02791072.1986.10472364.
    1. Wolfson, P. in MAPS Bulletin Winter Vol. 25 28–29 (MAPS, 2015).
    1. Carhart-Harris RL, et al. The effect of acutely administered MDMA on subjective and BOLD-fMRI responses to favourite and worst autobiographical memories. Int. J. Neuropsychopharmacol. 2014;17:527–540. doi: 10.1017/S1461145713001405.
    1. Hysek CM, et al. MDMA enhances emotional empathy and prosocial behavior. Soc. Cogn. Affect Neurosci. 2014;9:1645–1652. doi: 10.1093/scan/nst161.
    1. Dumont GJ, et al. Increased oxytocin concentrations and prosocial feelings in humans after ecstasy (3,4-methylenedioxymethamphetamine) administration. Soc. Neurosci. 2009;4:359–366. doi: 10.1080/17470910802649470.
    1. van Wel JH, et al. Effects of acute MDMA intoxication on mood and impulsivity: role of the 5-HT(2) and 5-HT(1) receptors. PLoS ONE. 2012;7:e40187. doi: 10.1371/journal.pone.0040187.
    1. Mithoefer MC, et al. MDMA-assisted psychotherapy for treatment of PTSD: study design and rationale for phase 3 trials based on pooled analysis of six phase 2 randomized controlled trials. Psychopharmacology. 2019;236:2735–2745. doi: 10.1007/s00213-019-05249-5.
    1. Vizeli P, Liechti ME. Safety pharmacology of acute MDMA administration in healthy subjects. J. Psychopharmacol. 2017;31:576–588. doi: 10.1177/0269881117691569.
    1. Wolfson, P. E. & Mithoefer, M. C. (MAPS, Santa Cruz, CA , 2015).
    1. Kolokotroni P, Anagnostopoulos F, Tsikkinis A. Psychosocial factors related to posttraumatic growth in breast cancer survivors: a review. Women Health. 2014;54:569–592. doi: 10.1080/03630242.2014.899543.
    1. Gesser, G., Wong, P. T. P. & Reker, G. T. Death attitudes across the life span: The development and validation of the Death Attitude Profile (DAP). Omega (Westport)18, 113–128 (1987–1988).
    1. Neff K. The Development and validation of a scale to measure self-compassion. Self Identity. 2003;2:223–250. doi: 10.1080/15298860309027.
    1. Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia Classification Algorithm of Suicide Assessment (C-CASA): classification of suicidal events in the FDA's pediatric suicidal risk analysis of antidepressants. Am. J. Psychiatry. 2007;164:1035–1043. doi: 10.1176/ajp.2007.164.7.1035.

Source: PubMed

スポンサーと協力者

医学的状態

薬物療法

3
購読する