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

Michael C Mithoefer, Mark T Wagner, Ann T Mithoefer, Lisa Jerome, Scott F Martin, Berra Yazar-Klosinski, Yvonne Michel, Timothy D Brewerton, Rick Doblin, Michael C Mithoefer, Mark T Wagner, Ann T Mithoefer, Lisa Jerome, Scott F Martin, Berra Yazar-Klosinski, Yvonne Michel, Timothy D Brewerton, Rick Doblin

Abstract

We report follow-up data evaluating the long-term outcomes for the first completed trial of 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for chronic, treatment-resistant post-traumatic stress disorder (PTSD) (Mithoefer et al., 2011). All of the 19 subjects who received MDMA-assisted treatment in the original trial participated in the long-term follow-up (LTFU), with 16 out of 19 completing all of the long-term outcome measures, which were administered from 17 to 74 months after the original study's final MDMA session (mean = 45.4; SD = 17.3). Our primary outcome measure used was the Clinician-Administered PTSD Scale (CAPS). Secondary outcome measures were the Impact of Events Scale-Revised (IES-R) and the Neuroticism Extroversion Oppenness Personality Inventory-Revised (NEO PI-R) Personality Inventory. We also collected a long-term follow-up questionnaire. Results for the 16 CAPS completers showed there were no statistical differences between mean CAPS score at LTFU (mean = 23.7; SD = 22.8) (t (matched) = 0.1; df = 15, p = 0.91) and the mean CAPS score previously obtained at Study Exit (mean = 24.6, SD = 18.6). On average, subjects maintained statistically and clinically-significant gains in symptom relief, although two of these subjects did relapse. It was promising that we found the majority of these subjects with previously severe PTSD who were unresponsive to existing treatments had symptomatic relief provided by MDMA-assisted psychotherapy that persisted over time, with no subjects reporting harm from participation in the study.

Conflict of interest statement

Conflict of interest: Our sponsor played a role in the study design, data analysis and writing of the report (the investigators performed all data collection). Three authors, Berra Yazar-Klosinski, Lisa Jerome and Rick Doblin, are employed by the sponsor. Michael Mithoefer is a medical monitor for other studies of MDMA-assisted psychotherapy that are currently being conducted by the sponsor. He and Ann Mithoefer both received payment from the sponsor for conducting this research, while also working on the development of a treatment manual, investigator training program, and the design of protocols for additional studies planned by the sponsor. The sponsor paid Mark Wagner for acting as the independent rater for this study.

Figures

Figure 1.
Figure 1.
Study design with number of participants.

References

    1. American Psychiatric Association (2000) Diagnostic and Statistical Manual of Mental Disorders. Arlington, VA: American Psychiatric Association
    1. Bartz JA, Hollander E. (2006) The neuroscience of affiliation: Forging links between basic and clinical research on neuropeptides and social behavior. Horm Behav 50: 518–528
    1. Bedi G, Hyman D, De Wit H. (2010) Is ecstasy an “empathogen”? Effects of +/-3,4-methylenedioxymethamphetamine on prosocial feelings and identification of emotional states in others. Biol Psychiatry 68: 1134–1140
    1. Bedi G, Phan KL, Angstadt M, et al. (2009) Effects of MDMA on sociability and neural response to social threat and social reward. Psychopharmacology (Berl) 207: 73–83
    1. Bedi G, Redman J. (2008) Ecstasy use and higher-level cognitive functions: Weak effects of ecstasy after control for potential confounds. Psychol Med 38: 1319–1330
    1. Benedek DM, Friedman MJ, Zatzick DF, et al. (2009) Guideline watch (March 2009): Practice guideline for the treatment of patients with acute stress disorder and posttraumatic stress disorder. In: Psychiatry Online. Available at: (accessed 23 July 2012).
    1. Benedetti F, Amanzio M. (2011) The placebo response: How words and rituals change the patient’s brain. Patient Educ Couns 84: 413–419
    1. Bjorkedal E, Flaten MA. (2011) Interaction between expectancies and drug effects: An experimental investigation of placebo analgesia with caffeine as an active placebo. Psychopharmacology (Berl) 215: 537–548
    1. Bouso JC, Doblin R, Farre M, et al. (2008) MDMA-assisted psychotherapy using low doses in a small sample of women with chronic posttraumatic stress disorder. J Psychoact Drugs 40: 225–236
    1. Brady K, Pearlstein T, Asnis GM, et al. (2000a) Efficacy and safety of sertraline treatment of posttraumatic stress disorder: A randomized controlled trial. JAMA 283: 1837–1844
    1. Brady KT, Killeen TK, Brewerton T, et al. (2000b) Comorbidity of psychiatric disorders and posttraumatic stress disorder. J Clin Psychiatry 61: 22–32
    1. Breslau N. (2001) The epidemiology of posttraumatic stress disorder: What is the extent of the problem? J Clin Psychiatry 62: 16–22
    1. Brewerton TD, Eyerman JE, Cappeta P, et al. (2011) Long-term abstinence following holotropic breathwork as adjunctive treatment of substance use disorders and related psychiatric comorbidity. Int J Mental Health Addiction 10: 453–459.
    1. Brown J, McKone E, Ward J. (2010) Deficits of long-term memory in ecstasy users are related to cognitive complexity of the task. Psychopharmacology (Berl) 209: 51-67
    1. Brown PJ, Wolfe J. (1994) Substance abuse and post-traumatic stress disorder comorbidity. Drug Alcohol Depend 35: 51–59
    1. Cami J, Farre M, Mas M, et al. (2000) Human pharmacology of 3,4-methylenedioxymethamphetamine (“ecstasy”): Psychomotor performance and subjective effects. J Clin Psychopharmacol 20: 455–466
    1. Costa PT, Macrae RR. (1992) NEO PI-R professional manual. Odessa, FL: Psychological Assessment Resources
    1. Davidson J, Pearlstein T, Londborg P, et al. (2001) Efficacy of sertraline in preventing relapse of posttraumatic stress disorder: Results of a 28-week double-blind, placebo-controlled study. Am J Psychiatry 158: 1974–1981
    1. De Sola Llopis S, Miguelez-Pan M, Pena-Casanova J, et al. (2008) Cognitive performance in recreational ecstasy polydrug users: A two-year follow-up study. J Psychopharmacol 22: 498–510
    1. Dorrepaal E, Thomaes K, Smit JH, et al. (2010) Stabilizing group treatment for complex posttraumatic stress disorder related to childhood abuse based on psycho-education and cognitive behavioral therapy: A pilot study. Child Abus Negl 34: 284–288
    1. Dumont GJ, Sweep FC, Van der Steen R, et al. (2009) Increased oxytocin concentrations and prosocial feelings in humans after ecstasy (3,4-methylenedioxymethamphetamine) administration. Social Neurosci 4: 359–366
    1. Edmond T, Rubin A. (2004) Assessing the long-term effects of EMDR: Results from an 18-month follow-up study with adult female survivors of CSA. J Child Sex Abus 13: 69–86
    1. Farre M, Abanades S, Roset PN, et al. (2007) Pharmacological interaction between 3,4-methylenedioxymethamphetamine (ecstasy) and paroxetine: Pharmacological effects and pharmacokinetics. J Pharmacol Exp Ther 323: 954–962
    1. Foa EB, Keane TM, Friedman MJ, et al. (2009) Effective Treatments for PTSD, Practice Guidelines from the International Society for Traumatic Stress Studies. New York: Guilford Press
    1. Ford JD, Hawke J, Alessi S, et al. (2007) Psychological trauma and PTSD symptoms as predictors of substance dependence treatment outcomes. Behav Res Ther 45: 2417–2431
    1. Gamma A, Buck A, Berthold T, et al. (2000) 3,4-Methylenedioxymethamphetamine (MDMA) modulates cortical and limbic brain activity as measured by [H(2)(15)O]-PET in healthy humans. Neuropsychopharmacol 23: 388–395
    1. Gouzoulis-Mayfrank E, Daumann J. (2006) Neurotoxicity of methylenedioxyamphetamines (MDMA; ecstasy) in humans: How strong is the evidence for persistent brain damage? Addiction 101: 348–361
    1. Greer G, Tolbert R. (1986) Subjective reports of the effects of MDMA in a clinical setting. J Psychoact Drugs 18: 319-327
    1. Griffiths RR, Richards WA, McCann U, et al. (2006) Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance. Psychopharmacology (Berl) 187: 268–292
    1. Halpern JH, Pope HG, Sherwood AR, et al. (2004) Residual neuropsychological effects of illicit 3,4-methylenedioxymethamphetamine (MDMA) in individuals with minimal exposure to other drugs. Drug Alcohol Depend 75: 135–147
    1. Halpern JH, Sherwood AR, Hudson JI, et al. (2011) Residual neurocognitive features of long-term ecstasy users with minimal exposure to other drugs. Addiction 106: 777–786
    1. Hanson KL, Luciana M. (2010) Neurocognitive impairments in MDMA and other drug users: MDMA alone may not be a cognitive risk factor. J Clin Exp Neuropsychol 32: 337–349
    1. Harris DS, Baggott M, Mendelson JH, et al. (2002) Subjective and hormonal effects of 3,4-methylenedioxymethamphetamine (MDMA) in humans. Psychopharmacology (Berl) 162: 396–405
    1. Health and Human Services (2011) Certificates of confidentiality kiosk. Available at: (accessed 30 November 2011).
    1. Hertzberg MA, Feldman ME, Beckham JC, et al. (2002) Three- to four-year follow-up to an open trial of nefazodone for combat-related posttraumatic stress disorder. Ann Clin Psychiatry 14: 215–221
    1. Hogberg G, Pagani M, Sundin O, et al. (2008) Treatment of post-traumatic stress disorder with eye movement desensitization and reprocessing: Outcome is stable in 35-month follow-up. Psychiatry Res 159: 101–108
    1. Hoshi R, Mullins K, Boundy C, et al. (2007) Neurocognitive function in current and ex-users of ecstasy in comparison to both matched polydrug-using controls and drug-naive controls. Psychopharmacology (Berl) 194: 371–379
    1. Hysek CM, Domes G, Liechti ME. (2012) MDMA enhances “mind reading” of positive emotions and impairs “mind reading” of negative emotions. Psychopharmacol 222: 293–302
    1. Jager G, De Win MM, Van der Tweel I, et al. (2008) Assessment of cognitive brain function in ecstasy users and contributions of other drugs of abuse: Results from an FMRI study. Neuropsychopharmacol 33: 247–258
    1. Johnson DR, Rosenheck R, Fontana A, et al. (1996) Outcome of intensive inpatient treatment for combat-related posttraumatic stress disorder. Am J Psychiatry 153: 771–777
    1. Kalechstein AD, De la, Garza R, Mahoney JJ, et al. (2007) MDMA use and neurocognition: A meta-analytic review. Psychopharmacology (Berl) 189: 531–537
    1. Kessler RC, Chiu WT, Demler O, et al. (2005) Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 62: 617–627
    1. Kirkpatrick MG, Gunderson EW, Perez AY, et al. (2012) A direct comparison of the behavioral and physiological effects of methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA) in humans. Psychopharmacology (Berl) 219: 109–122
    1. Kish SJ, Lerch J, Furukawa Y, et al. (2010) Decreased cerebral cortical serotonin transporter binding in ecstasy users: A positron emission tomography/[(11)C]DASB and structural brain imaging study. Brain 133: 1779–1797
    1. Kolbrich EA, Goodwin RS, Gorelick DA, et al. (2008) Physiological and subjective responses to controlled oral 3,4-methylenedioxymethamphetamine administration. J Clin Psychopharmacol 28: 432–440
    1. Laws KR, Kokkalis J. (2007) Ecstasy (MDMA) and memory function: A meta-analytic update. Hum Psychopharmacol
    1. Liechti ME, Baumann C, Gamma A, et al. (2000) Acute psychological effects of 3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”) are attenuated by the serotonin uptake inhibitor citalopram. Neuropsychopharmacol 22: 513–521
    1. Liechti ME, Gamma A, Vollenweider FX. (2001a) Gender differences in the subjective effects of MDMA. Psychopharmacology (Berl) 154: 161–168
    1. Liechti ME, Vollenweider FX. (2001b) Which neuroreceptors mediate the subjective effects of MDMA in humans? A summary of mechanistic studies. Hum Psychopharmacol 16: 589–598
    1. MAPS (2009) Long-term follow-up questionnaire for phase II study of MDMA-assisted psychotherapy for PTSD. Available at: (accessed 23 July 2012).
    1. Marshall RD, Beebe KL, Oldham M, et al. (2001) Efficacy and safety of paroxetine treatment for chronic PTSD: A fixed-dose, placebo-controlled study. Am JPsychiatry 158: 1982–1988
    1. Mithoefer MC, Jerome L, Ruse JM, et al. (2011) MDMA-assisted psychotherapy for the treatment of posttraumatic stress disorder: A revised teaching manual draft. Available at: (accessed 23 July 2012).
    1. Mithoefer MC, Wagner MT, Mithoefer AT, et al. (2011) 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 25: 439–452
    1. Olff M, Langeland W, Witteveen A, et al. (2010) A psychobiological rationale for oxytocin in the treatment of posttraumatic stress disorder. CNS Spectrums 15: 522–530
    1. Peleg T, Shalev AY. (2006) Longitudinal studies of PTSD: Overview of findings and methods. CNS Spectrums 11: 589–602
    1. Perkonigg A, Kessler RC, Storz S, et al. (2000) Traumatic events and post-traumatic stress disorder in the community: Prevalence, risk factors and comorbidity. Acta Psychiatrica Scand 101: 46–59
    1. Pitman RK, Orr SP, Lasko NB. (1993) Effects of intranasal vasopressin and oxytocin on physiologic responding during personal combat imagery in Vietnam veterans with posttraumatic stress disorder. Psychiatry Res 48: 107–117
    1. Price DD, Finniss DG, Benedetti F. (2008) A comprehensive review of the placebo effect: Recent advances and current thought. Annu Rev Psychol 59: 565–590
    1. Rapaport MH, Endicott J, Clary CM. (2002) Posttraumatic stress disorder and quality of life: Results across 64 weeks of sertraline treatment. J Clin Psychiatry 63: 59–65
    1. Rauch SL, Shin LM, Phelps EA. (2006) Neurocircuitry models of posttraumatic stress disorder and extinction: Human neuroimaging research–past, present, and future. Biol Psychiatry 60: 376–382
    1. Rogers G, Elston J, Garside R, et al. (2009) The harmful health effects of recreational ecstasy: A systematic review of observational evidence. Health Technol Assess 13: 1–315
    1. Roiser JP, Rogers RD, Sahakian BJ. (2007) Neuropsychological function in ecstasy users: A study controlling for polydrug use. Psychopharmacology (Berl) 189: 505–516
    1. Sackeim HA, Haskett RF, Mulsant BH, et al. (2001) Continuation pharmacotherapy in the prevention of relapse following electroconvulsive therapy: A randomized controlled trial. JAMA 285: 1299–1307
    1. Schilt T, De Win MM, Jager G, et al. (2008) Specific effects of ecstasy and other illicit drugs on cognition in poly-substance users. Psychol Med 38: 1309–1317
    1. Schilt T, De Win MM, Koeter M, et al. (2007) Cognition in novice ecstasy users with minimal exposure to other drugs: a prospective cohort study. Arch Gen Psychiatry 64: 728–736
    1. Seal KH, Maguen S, Cohen B, et al. (2010) VA mental health services utilization in Iraq and Afghanistan veterans in the first year of receiving new mental health diagnoses. J Traumatic Stress 23: 5–16
    1. Setola V, Hufeisen SJ, Grande-Allen KJ, et al. (2003) 3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”) induces fenfluramine-like proliferative actions on human cardiac valvular interstitial cells in vitro. Molec Pharmacol 63: 1223–1229
    1. Sienaert P. (2011) What we have learned about electroconvulsive therapy and its relevance for the practising psychiatrist. Canad J Psychiatry 56: 5–12
    1. Solomon Z, Shklar R, Mikulincer M. (2005) Frontline treatment of combat stress reaction: A 20-year longitudinal evaluation study. Am J Psychiatry 162: 2309–2314
    1. Stein DJ, Ipser J, McAnda N. (2009) Pharmacotherapy of posttraumatic stress disorder: A review of meta-analyses and treatment guidelines. CNS Spectrums 14: 25–31
    1. Studerus E, Gamma A, Vollenweider FX. (2010) Psychometric evaluation of the altered states of consciousness rating scale (OAV). PLoS One 5: e12412.
    1. Tancer M, Johanson CE. (2003) Reinforcing, subjective, and physiological effects of MDMA in humans: A comparison with d-amphetamine and mCPP. Drug Alcohol Depend 72: 33–44
    1. Tedeschi RG, Calhoun LG. (1996) The posttraumatic growth inventory: Measuring the positive legacy of trauma. J Traumatic Stress 9: 455–471
    1. Tedeschi RG, Calhoun LG. (2006) Expert comparisons; Posttraumatic growth in clinical practice. In: Calhoun LG, Tedeschi RG. (eds) Handbook of Posttraumatic Growth: Research and Practice Mahwah, NJ: Erlbaum, pp. 291–310
    1. Thomasius R, Zapletalova P, Petersen K, et al. (2006) Mood, cognition and serotonin transporter availability in current and former ecstasy (MDMA) users: The longitudinal perspective; J Psychopharmacol 20: 211–225
    1. Ursano RJ, Bell C, Eth S, et al. (2004) Practice guideline for the treatment of patients with acute stress disorder and posttraumatic stress disorder. Am J Psychiatry 161: 3–31
    1. Van der Kolk BA, Spinazzola J, Blaustein ME, et al. (2007) A randomized clinical trial of eye movement desensitization and reprocessing (EMDR), fluoxetine, and pill placebo in the treatment of posttraumatic stress disorder: Treatment effects and long-term maintenance. J Clin Psychiatry 68: 37–46
    1. Verbaten MN. (2010) Deterioration of executive functioning in chronic ecstasy users; evidence for multiple drugs effects. Curr Drug Abuse Rev 3: 129–138
    1. Weathers FW, Keane TM, Davidson JR. (2001) Clinician-administered PTSD scale: A review of the first ten years of research. Depress Anxiety 13: 132–156
    1. Weiss DS, Marmar CR. (1996) The Impact of Event Scale - Revised. In: Wilson J, Keane TM. (eds) Assessing psychological trauma and PT SD. New York: Guilford, pp.399–411
    1. Wolff K, Tsapakis EM, Winstock AR, et al. (2006) Vasopressin and oxytocin secretion in response to the consumption of ecstasy in a clubbing population. J Psychopharmacol 20: 400–410
    1. Zakzanis KK, Campbell Z, Jovanovski D. (2007) The neuropsychology of ecstasy (MDMA)use: A quantitative review. Hum Psychopharmacol 22: 427–435
    1. Zimmermann P, Biesold KH, Barre K, et al. (2007) Long-term course of post-traumatic stress disorder (PTSD) in German soldiers: Effects of inpatient eye movement desensitization and reprocessing therapy and specific trauma characteristics in patients with non-combat-related PTSD. Mil Med 172: 456–460
    1. Zoellner T, Maercker A. (2006) Posttraumatic growth in clinical psychology - A critical review and introduction of a two component model. Clin Psychol Rev 26: 626–653

Source: PubMed

스폰서 및 공동 작업자

건강 상태

약물 개입

3
구독하다