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research-article2014
AOPXXX10.1177/1060028014532236Annals of PharmacotherapyWhite
Article
3,4-Methylenedioxymethamphetamine’s (MDMA’s) Impact on Posttraumatic Stress Disorder
Annals of Pharmacotherapy 1–8 © The Author(s) 2014 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028014532236 aop.sagepub.com
C. Michael White, PharmD, FCP, FCCP1
Abstract Objective: Review the current literature assessing the role of 3,4-methylenedioxymethamphetamine (MDMA) on posttraumatic stress disorder (PTSD). Data Sources: OVID MEDLINE search (1960-February 2014) using the terms MDMA, 3,4-methylenedioxymethamphetamine, Molly, and Ecstasy crossed with posttraumatic stress disorder with backwards citation tracking using references from procured articles. Study Selection and Data Extraction: English language studies assessing MDMA in patients with PTSD. Data Synthesis: Three randomized controlled trials (RCTs) were conducted along with follow-up open-label and extension evaluations. In the 3 RCTs, therapy with MDMA-assisted psychotherapy is promising, with reductions in PTSD rating scale scores (Clinician-Administered PTSD Scale, Severity of Symptoms Scale for PTSD Scale), although 2 of 3 trials did not show significant results, and all three had methodological limitations. The direction of effect for all trials was toward benefit in patients who were refractory to other PTSD therapies; the percentage reductions on rating scores ranged from 23% to 68%; and in 1 trial, the effect was sustained over a long period of time. MDMA ingestion without sustained psychotherapy over a 6- to 8-hour period is unlikely to be beneficial; trying to prolong the duration of effect with supplemental dosing is unlikely to provide additional benefits; and there are adverse effects on blood pressure and heart rate that should be appreciated. These studies used unadulterated MDMA with known and reproducible potency, which may not happen with street purchase of the product. Conclusions: MDMA-assisted psychotherapy may be an effective therapy in refractory PTSD but needs further evaluation to determine its place in contemporary therapy. Keywords PTSD, posttraumatic stress disorder, MDMA, Molly/Ecstasy, psychotherapy
Background Over their lifetime, 8% to 9% of the general population will develop posttraumatic stress disorder (PTSD), with women having twice the risk as men.1-3 However, the type of traumatic event greatly affects the risk of developing PTSD. The most common types of traumatic events resulting in PTSD include being held as a prisoner of war, rape, combat, physical traumatic assault, nonrape sexual assault, and serious accident/injury, with lifetime prevalence rates of 78%, 49%, 39%, 32%, 24%, and 17%, respectively.1-4 The trauma can be directly experienced (person in combat), personally witnessed (seeing someone beaten or murdered), or experienced vicariously through exposure of a loved one experiencing a traumatic event.1,5 PTSD chronically induces 3 types of symptom clusters: (1) intrusion symptoms (flashbacks, nightmares, and recurrent vivid images related to the event); (2) negative alterations in cognition/mood (inability to recall important details of the event or negative beliefs about self and situation); (3) avoidance and dissociation symptoms (avoiding situations
of events that trigger flashbacks and feeling emotionally disconnected from current events or other people); and (4) changes in arousal and reactivity (exaggerated startle response, excessive vigilance against danger, insomnia, and poor concentration).5 The Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Criterion A2 regarding the subjective reaction to the traumatic event, specifically intense fear, helplessness, or horror, has been eliminated because first responders and the military are trained to avoid this reaction.5 In this article, we will briefly review the current state of prescription pharmacotherapy and psychotherapy for PTSD, discuss the unique pharmacological effects of 3,4-methylenedioxymethamphetamine (MDMA) that could 1
University of Connecticut School of Pharmacy, Hartford, CT, USA
Corresponding Author: C. Michael White, Department of Pharmacy Practice, University of Connecticut School of Pharmacy, 69 N Eagleville Rd, Storrs, CT 062693092, USA. Email: [email protected]
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Table 1. Rating Scales Used in MDMA PTSD Studies.7,8 Rating Scale Severity of Symptoms Scale for PTSD (SSSPTSD) Clinician-Administered PTSD Scale (CAPS)
Components Two scales with each item in a scale rated as 0, 1, 2, or 3. Higher scores denote worse PTSD •• A 17-item Core Rating Scale (total score 0 to 51) 5 Items on reexperiencing symptoms 7 Items on avoidance symptoms 5 Items on arousal symptoms •• A 13-item supplementary scale (total score 0 to 39) Scale with each item rated on a 0 to 4 Likert scale for frequency (never to nightly or always) and intensity (none to extreme, overwhelming, or incapacitating). Higher scores denote worse PTSD with a score of >50 signifying moderate to severe disease •• 30-item CAPS-1 Scale 17 Items on symptoms of PTSD 8 Items on associated symptoms 5 Items on the impact of symptoms on societal functioning, improvement in PTSD symptoms since a previous assessment, overall response validity, and overall PTSD severity
Abbreviations: MDMA, 3,4-methylenedioxymethamphetamine; PTSD, posttraumatic stress disorder.
affect PTSD or the risk profile of MDMA, review in detail the clinical trials assessing MDMA in PTSD, and then briefly discuss issues associated with procuring and using MDMA outside of a clinical trial setting.
Current Pharmacotherapeutic and Psychotherapeutic Options for PTSD Several medications have been investigated for patients with PTSD, but only the selective serotonin reuptake inhibitors (SSRIs) paroxetine and sertraline have a Food and Drug Administration indication for the disorder.6 A systematic review of 37 randomized controlled trials (RCTs) comprising 5008 patients being treated for PTSD with prescription medication (SSRIs, venlafaxine, nefazodone, risperidone, topiramate, divalproex, tiagabine, prazosin, olanzapine, risperidone) was published in 2012. The main outcome measure was the impact on the Clinician Administered PTSD Scale (CAPS), the gold standard assessment scale, with reductions in score from baseline denoting improvements.6 A brief review of PTSD rating scales is given in Table 1.7,8 The SSRIs (citalopram, fluoxetine, paroxetine, and sertraline; −6.64 [95% CI = −9.11 to −4.16]) and venlafaxine (−8.11 [−12.30 to −3.92]) significantly affected CAPS score mean differences with moderate and minimal statistical heterogeneity (I2 statistics of 30%-50% and 15 (Table 1).7,8 Whereas the proposed sample size was 29 and was supposed to have patients randomized to 50, 75, 100, 125, and 150 mg or placebo, the study was reportedly terminated as a result of political pressure in Spain after only 6 patients were enrolled.24 Of these, 3 received 50 mg of MDMA, 1 received 75 mg MDMA, and 2 received placebo as a result of randomization. All underwent 7 psychotherapy sessions of 90 minutes’ duration, with only 1 session accompanied by MDMA or placebo. This psychotherapy session (session 4 of 8) began with MDMA ingestion and lasted for 6 hours, with patients resting for 2 additional hours after this psychotherapy session before being driven home. The authors did not conduct statistical analyses, but there were baseline and immediate postpsychotherapy data for all 6 participants (Table 2).24,27-29 The overall SSSPTSD scale scores were reduced by an average of 26.8% with MDMA plus psychotherapy and 10.1% with placebo plus psychotherapy, driven by larger reductions in the reexperiencing and avoidance subscales but similar reductions in the arousal and supplemental scales between the 2 groups.24 With only 1 patient receiving 75 mg of MDMA, assessing for a dose response effect is not prudent.
The second study by Mithoefer et al27 was a randomized, double-blind, placebo-controlled trial assessing the impact of 125-mg MDMA-assisted psychotherapy in refractory patients with PTSD (95% crime and 5% combat related trauma, 85% female, 100% Caucasian, 80% comorbid major depression). Patients underwent 11 regular nondrug psychotherapy sessions of 90 minutes’ duration along with 2 MDMA 125-mg or placebo sessions (sessions 5 and 11) of 8 to 10 hours followed by an overnight stay (zolpidem or lorazepam could be given for sleep that night if desired).27 Toward the end of the study, an amendment was approved allowing for a supplemental dose of MDMA of 62.5 mg or placebo in sessions 5 or 11 if investigators and participants agreed. The supplemental dose was administered to 4 participants in the MDMA group but no placebo patients, suggesting that participants and investigators were able to discern which group received MDMA and which received placebo. Overall, 23 patients were randomized (MDMA, n = 15; placebo, n = 8), but 2 MDMA patients dropped out (one for relapse of depression and another for unwillingness to travel), and another MDMA patient was judged not to be treatment resistant and did not receive MDMA therapy. The primary outcome was the impact of MDMA on the CAPS questionnaire taken at baseline, 4 days after each experimental session, and 2 months after the second experimental session. MDMA effects were perceptible at 45 to 75 minutes, peaked at 2 to 2.5 hours, and were gone by 4 to 5 hours in the nonsupplemented and 5 to 6 hours in the supplemented group. Mean CAPS scores were reduced at all follow-up times in both groups (group vs time interaction P < 0.001) but to a greater extent in the MDMA group versus the placebo group (group vs time interaction, P = 0.015; 67.8% reduction vs 25.8% reduction at 2 months after experimental session 2; Table 1).24,27-29 Investigators defined a clinically significant response as a >30% reduction in CAPS score, with 83.3% (10 of 12 patients) and 25.0% (2 of 8 patients) of MDMA and placebo patients achieving that level of benefit (P = 0.019; self-calculated, Primer of Statistics, Version 4.02, NY). There were no additional benefits on CAPS scores from using supplemental doses (group vs time interaction, P = 0.637).27 There were significantly greater maximum elevations in systolic (25.2 ± 13.7 vs 22.2 ± 15.3 mm Hg, P < 0.05) and diastolic blood pressures (14. 4 ± 6.5 vs 13.8 ± 7.5 mm Hg, P < 0.05), pulse (28.8 ± 11.5 vs 22.2 ± 13.7 bpm, P < 0.05), and temperature (0.5 ± 0.4 vs −0.7 ± 0.6, P < 0.05) versus baseline, but there were no significant differences by 6 hours after dosing. Investigators did not determine whether the use of supplemental MDMA dosing caused a different magnitude of hemodynamic effects versus standard doses alone.27 After the RCT, investigators established an open-label trial where patients receiving placebo could receive MDMA using the same protocol.27 In this open label MDMA
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23 (Three MDMA patients did not complete therapy)
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Patient Number
Treatment Regimen
MDMA given during two 8-hour experimental psychotherapy sessions to those previously given placebo MDMA 125 mg (n = 16) Comparison of longterm follow-up results of patients given MDMA versus 2 months post-MDMA therapy MDMA 25 mg + 12.5 mg MDMA or placebo given during three 2.5 hours later (n = 8-hour experimental 4); MDMA 125 mg + psychotherapy sessions 62.6 mg 2.5 hours later (n = 8)
MDMA 125 mg (n = 7)
MDMA 125 mg (n = 12); MDMA or placebo placebo (n = 8) given during two 8-hour experimental psychotherapy sessions
MDMA 50-75 mg MDMA or Placebo (n = 4); placebo (n = 2) given during one 6-hour experimental psychotherapy session
Treatment Groups
CAPS
CAPS
CAPS
CAPS
SSSPTSD
Primary Measure
High dose vs low dose •• CAPS baseline: 66.4 ± 13.6 vs 63.4 ± 7.9 •• CAPS session 2: 63.0 ± 17.8 vs 60.0 ± 6.8 •• CAPS session 3: 50.8 ± 19.7 vs 66.5 ± 7.6 Trend toward greater effects from higher-dose MDMA; 2-way ANOVA P = 0.066
2 Months post-MDMA vs 17-71 months Post-MDMA •• CAPS 2 months Post-MDMA: 23.7 ± 22.8 •• CAPS long-term post-MDMA: 24.6 ± 18.6 CAPS scores post-MDMA similar in the short and long term; P = 0.91
•• MDMA vs placebo SSSPTSD baseline: 40.0 ± 7.0 vs 44.5 ± 7.1 •• SSSPTSD posttherapy: 29.3 ± 8.7 vs 40.0 ± 1.4 •• SSSPTSD RE baseline: 12.8 ± 3.2 vs 12.5 ± 7.1 •• SSSPTSD RE post: 11.0 ± 4.5 vs 12.0 ± 1.4 •• SSSPTSD A baseline: 16.8 ± 2.6 vs 15.0 ± 2.8 •• SSSPTSD A post: 11.0 ± 4.1 vs 16.0 ± 0.0 •• SSSPTSD AI baseline: 10.5 ± 3.1 vs 14.0 ± 1.4 •• SSSPTSD AI post: 7.3 ± 1.7 vs 12.0 ± 0.0 •• SSSPTSD SS baseline: 24.3 ± 9.3 vs 25.0 ± 4.2 •• SSSPTSD SS post: 17.3 ± 8.7 vs 18.5 ± 13.4 P values not calculated because of small patient numbers, different MDMA doses administered, and unequal distribution between groups •• MDMA vs placebo CAPS baseline: 79.2 ± 6.6 vs 79.6 ± 8.1 •• CAPS session 1: 37.8 ± 8.4 vs 74.1 ± 10.3 •• CAPS session 2: 29.3 ± 6.5 vs 66.8 ± 8.0 •• CAPS 2 months post: 25.5 ± 7.7 vs 59.1 ± 9.4 Group vs time interaction showed greater improvements for MDMA than placebo (P = 0.015) •• Baseline vs MDMA CAPS baseline: 65.6 ± 24.4 •• CAPS 2 months post MDMA: 33.9 ± 12.8 CAPS scores significantly reduced with MDMA use versus baseline in patients previously receiving placebo; P < 0.05
Results (MDMA vs Placebo)
Abbreviations: MDMA, 3,4-methylenedioxymethamphetamine; PTSD, posttraumatic stress disorder; DB, double blind; PC, placebo control; SSSPTSD, Severity of Symptoms Scale for PTSD Scale; RE, re-experiencing; A, avoidance; AI, arousal increased; SS, supplemental scale; CAPS, Clinician-Administered PTSD Scale; OL, open label; AC, active control; R, randomized.
Oehen et al29 14 (2 Participants (2013), R, DB, AC dropped out of the trial, 1 per arm)
Mithoefer et al27 7 (2011) single arm, OL (OL study of Mithoefer et al27 above) Mithoefer et al28 19 (3 Participants did (2013), single arm, not complete the OL (OL extension long-term follow-up study of Mithoefer questionnaire) et al27 above)
Mithoefer et al27 (2011), R, DB, PC
Bouso et al (2008), R, DB, PC
Reference (Year), Trial Type
Table 2. Clinical Trials of MDMA in PTSD.24,27-29
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evaluation, 7 individuals participated, and all of them had evaluable data. Participants were eligible for the supplemental MDMA dose of 62.5 mg, and 4 individuals received it. MDMA reduced the mean CAPS score from the postplacebo baseline period to the 2-month post-MDMA open-label time period (65.6 ± 24.4 vs 33.9 ± 12.8, P < 0.05). All the participants had a clinically significant reduction of >30% versus the initial preplacebo baseline CAPS score. Investigators did not report whether supplemental doses affected results.27 All 19 patients utilizing MDMA (randomized trial + openlabel study) were asked to complete a long-term follow-up CAPS questionnaire.28 Of 19 patients, 16 completed the questionnaire (17 to 71 months after study completion), with the reasons for not completing the questionnaire reported as being lost to follow-up (n = 1), concern about triggering more symptoms (n = 1), and stressful family matters (n = 1). The one patient who did not want to trigger additional symptoms was reportedly the one who had the least benefit from MDMA during the initial study. The CAPS score at long-term followup in those completing the questionnaire approximated that seen 2 months after the experimental MDMA session 2 ended (23.7 ± 22.8 vs 24.6 ± 18.6, P = 0.91).28 The third study by Oehen et al29 was a randomized, double-blind comparison of psychotherapy assisted by low-dose MDMA (25 mg + 12.5-mg supplementary dose) versus high-dose MDMA therapy (125 mg + 62.5-mg supplementary dose).29 There were 3 experimental sessions where MDMA and psychotherapy was conducted over an 8-hour period (with an overnight stay) interspersed with 12 brief, nondrug psychotherapy sessions conducted weekly. CAPS scores were determined at baseline, 3 weeks after the second and third MDMA sessions, and 2 months and 1 year after the third MDMA session. Patients had to be refractory to other PTSD treatments. Of 12 individuals, 7 had experienced one or more evidence-based psychological therapies in the past (cognitive behavioral therapy, n = 3; exposure-based psychotherapy, n = 1; eye movement desensitization and reprocessing therapy, n = 1; and anxiety management therapy, n = 3). Also, 6 individuals had non–evidence-based psychotherapy such as insight-oriented therapy. Pharmacotherapy was reportedly used previously in patients but not specified, and individuals could not be on PTSD pharmacotherapy on entering the study. It was stated that many patients used multiple therapies in the past, so it was not possible for them to exactly identify each one. Chronic gabapentin was allowed for pain, and zolpidem and lorazepam could be used for sleep during experimental sessions. Two of 14 patients withdrew after receiving MDMA because of adverse events (1 in the low-dose and 1 in the high-dose MDMA groups) and had a different country of origin (Turkey and South Africa) than the others, who were all of European descent. The patient who dropped out while receiving low-dose MDMA reported dropping out because of feeling “overstressed by the process”; the reason for withdrawal in the other patient was not
specified. The remaining 12 patients (58% sexual assault and 0% war-related trauma, 83% female, 83% comorbid depression) had evaluable data. Of these, 8 patients received high-dose MDMA and 4 received low-dose MDMA. There was a non–statistically significant trend toward improved CAPS scores with high-dose versus Low-dose therapy (Table 2, 2-way ANOVA, P = 0.066).24,27-29 Patients on lowdose therapy had a higher CAPS score after the third session than they did at baseline, and the reductions in CAPS with high-dose therapy were most robust between experimental sessions 2 and 3 and were only modestly affected at the other time periods. The investigators stated that the low-dose MDMA group experienced spontaneous recall and relived traumatic events but without the positive and integrative effects of the high-dose MDMA state. They stated that using low-dose MDMA took more support from the therapists and was more trying for the participants than high-dose MDMA, but data to support this assertion was not provided. At 1 year of follow-up, CAPS scores were reportedly decreased by 24 points (35%) compared with baseline in the high-dose group, but statistical analysis was not conducted.29 There were no data at 1 year presented in the low-dose MDMA group. The investigators evaluated the impact on systolic and diastolic blood pressure, pulse, and temperature at baseline, maximum effects, and 8 hours, but statistical analysis was not completed.29 The maximum values for each parameter were higher than at baseline, with greater increases in highdose therapy versus Low-dose therapy for every parameter except temperature, which was similarly increased. The maximal increases in systolic blood pressure (134.3 ± 17.3 vs 160.1 ± 21.1 mm Hg) and pulse rate (79.7 ± 7.4 vs 98.5 ± 13.3 bpm) were especially marked in the high-dose MDMA group versus baseline. However, all elevations resolved by the 8-hour final evaluation.29 At the end of the RCT, the 4 individuals in the low-dose MDMA group were given high-dose MDMA in the openlabel phase, with results provided at 1 year follow-up. There was a 35-point decrease (52%) in the CAPS score in these 4 patients versus baseline (no statistical analysis conducted).29 For the 3 patients originally included in the high-dose MDMA group who did not exhibit much response from MDMA therapy, the clinicians were allowed to give them additional high-dose MDMA sessions at the conclusion of the RCT.29 The exact dose used was determined by clinical judgment, but the mean CAPS scores were only reduced by 0.3 points.
Issues in Acquiring and Using MDMA In 1985, the Drug Enforcement Agency labeled MDMA a schedule I drug (no approved medical use, high abuse potential, and illegal to possess), and the manufacture, transport, and sale of MDMA products are illegal.30 This illegality and the lack of regulation and oversight results in
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White MDMA products that vary widely in potency, can contain other drugs of abuse without disclosure to the buyers, or can be manufactured in unsanitary settings.31 From the early 1980s to the late 1990s, MDMA products went from being rarely contaminated with other substances to having a majority of tablets not containing MDMA but instead being composed of other amphetamine and psychedelic substances. Over the past several years, up to 90% of tablets sold as MDMA contain MDMA but may still be adulterated with other substances; also, the dosage of MDMA per tablet varied widely, from 20 to 150 mg.31 The main adverse effects of MDMA include cardiac events (myocardial infarction, stroke, and arrhythmia), hyponatremia, hyperpyrexia, rhabdomyolysis, and disseminated intravascular coagulopathy.31 Vigorous activity accentuates the pharmacological effects of MDMA and, therefore, the adverse event potential. MDMA use has been associated with neurotoxicity and hepatotoxicity. Although people have euphoric effects within a few hours of dosing, they have a prolonged depressed mood for several days thereafter arising from depletion of serotonin stores. Patients with coronary disease, uncontrolled hypertension, arrhythmias or genetic predisposition to arrhythmias, hyperpyrexia, liver cirrhosis, neurotoxicity, and hyponatremia should likely avoid MDMA therapy.31 Even if people could acquire a reliable and stable supply of MDMA and replicate the study procedures with methodological safeguards, the possession of MDMA by mental health professionals or patients is illegal and could result in arrest and/or imprisonment.
Conclusions MDMA-assisted psychotherapy is a promising therapy for refractory PTSD.24-29 The benefits may be appreciable and may be sustained over the longer term, but these clinical trials are preliminary, had methodological weaknesses, and are not definitive.24,27-29 It appears that 125 mg is an effective dose, mostly affecting reexperiencing and avoidance, and supplemental MDMA dosing is not beneficial.24,27 If patients do not respond to MDMA therapy by the end of the third assisted psychotherapy, additional MDMA sessions are unlikely to help.27,29 These results may not be applicable to all ethnic groups and for all PTSD causes. The only 2 withdrawals in the Oehen trial were in non-Europeans; the Mithoefer trial was conducted solely in Caucasians; and the ethnicity in the Bouso trial was not reported, but it was conducted in Spain.27,29 The current trials focus heavily on patients with sexual assault (in childhood or adulthood), and there is virtually no clinical trial experience in those with war-related causes of PTSD.24,27-29 Given the complexity of the protocol with 6- to 8-hour therapy sessions, therapists of both genders being present, and overnight stays, MDMAassisted psychotherapy may be cost prohibitive for some
people.24,27-29 Although MDMA assisted psychotherapy may be better than the same type of psychotherapy applied without MDMA, whether it would be superior to combined standard-of-care psychotherapy with SSRI therapy is unknown and should be the focus of a subsequent clinical trial. Anecdotally in the 3 trials, some patients originally unable to work were able to begin working again after MDMAassisted pharmacotherapy, but this was not a prespecified aim.24,27-29 Unlike the current pilot evidence, any follow-up study should use an intention-to-treat analysis, so that withdrawals are better captured and accounted for. The investigators should also have the freedom to analyze and report their results without the involvement of MAPS personnel. Patients who are currently receiving SSRIs, which are known to block much of the pharmacological effects of MDMA, might experience lackluster results such as those seen in the lower-dose MDMA group in the trial by Oehen et al29 and others.20 In the clinical trials for MDMA in PTSD, patients tapered off psychopharmacological therapy before they underwent study procedures, but they did not report on the impact of doing this on the majority of their patients with comorbid depression.24,27-29 There are adverse hemodynamic effects that might make MDMA use inappropriate in certain patients.27,29 Patients with uncontrolled hypertension, arrhythmias, coronary artery disease, or stroke might have untoward adverse effects from the elevations in blood pressure and pulse rate.31 MDMA and its metabolites are CYP and COMT metabolized, and MDMA is also a CYP2D6 inhibitor, so people with genetic polymorphisms or who are on interacting medications might be at risk of unpredictable effects.17,21 It should be noted that MDMA use gives people the feeling of having additional energy, but the combination of exercise and MDMA has been shown to accentuate the impact of therapy on blood pressure, heart rate, and the release of neurochemicals and hormones that can lead to adverse events.17 In the 3 PTSD trials, the researchers were very careful to monitor hemodynamics and temperature and to give patients instructions to rest during the 8-hour period, use relaxing music, and undergo introspection.24,27-29 MDMA-facilitated psychotherapy should be further studied for patients with PTSD but cannot be recommended for clinical use at the present time because of safety considerations, legal ramifications of its schedule I drug status, and the need for additional studies to assess the balance of benefits and harms.30,31 Declaration of Conflicting Interests The author declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author received no financial support for the research, authorship, and/or publication of this article.
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References 1. Breslau N, Davis GC, Andreski P, Peterson E. Traumatic events and posttraumatic stress disorder in an urban population of young adults. Arch Gen Psychiatry. 1991;48:216222. 2. Kessler RC, Sonnega A, Bromet E, Hughes M, Nelson CB. Posttraumatic stress disorder in the National Comorbidity Survey. Arch Gen Psychiatry. 1995;52:1048-1060. 3. Helzer JE, Robins LN, McEvoy L. Post-traumatic stress disorder in the general population: findings of the epidemiologic catchment area survey. N Engl J Med. 1987;317:1630-1634. 4. Sutker PB, Allain AN, Winstead DK. Psychopathology and psychiatric diagnoses of World War II Pacific theater prisoner of war survivors and combat veterans. Am J Psychiatry. 1993;150:240-245. 5. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Publishing; 2013. 6. Ipser JC, Stein DJ. Evidence-based pharmacotherapy of post-traumatic stress disorder (PTSD). Int J Neuropsychopharmacol. 2012;15:825-840. 7. Foa EB, Riggs DS, Dancu CV, Rothbaum BO. Reliability and validity of a brief instrument assessing post-traumatic stress disorder. J Trauma Stress. 1993;6:459-474. 8. Blake DD, Weathers FW, Nagy LM, et al. The development of a clinician-administered PTSD scale. J Trauma Stress. 1995;8:75-90. 9. Albucher RC, Liberzon I. Psychopharmacological treatment in PTSD: a critical review. J Psychiatry Res. 2002;36:355-367. 10. Gelpin E, Bonne O, Peri T, Brandes D, Shalev AY. Treatment of recent trauma survivors with benzodiazepines: a prospective study. J Clin Psychiatry. 1996;57:390-394. 11. Foa EB, Davidson JRT, Frances A. The expert consensus guideline series: treatment of posttraumatic stress disorder. J Clin Psychiatry. 1999;60(suppl 16):60-66. 12. Klein B, Meyer D, Austin DW, Kyrios M. Anxiety online: a virtual clinic: preliminary outcomes following completion of five fully automated treatment programs for anxiety disorders and symptoms. J Med Internet Res. 2011;13:e89. 13. Friedman MJ. Toward rational pharmacotherapy for posttraumatic stress disorder: an interim report. Am J Psychiatry. 1988;145:281-285. 14. Pitman RK, Altman B, Greenwald E, et al. Psychiatric complications during flooding therapy for posttraumatic stress disorder. J Clin Psychiatry. 1991;52:17-20. 15. Hetrick SE, Purcell R, Garner B, Parslow R. Combined pharmacotherapy and psychological therapies for post traumatic stress disorder (PTSD). Cochrane Database Syst Rev. 2010;(7):CD007316. doi:10.1002/14651858.CD007316.pub2. 16. Capela JP, Carmo H, Remiao, et al. Molecular and cellular mechanisms of ecstasy-induced neurotoxicity: an overview. Mol Neurobiol. 2009;39:210-271. 17. Rietjens SJ, Hondebrink L, Westerlink RHS, Meulenbelt J. Pharmacokinetics and pharmacodynamics of 3,4-methylenedioxymethamphetamine (MDMA): interindividual differences
due to polymorphisms and drug-drug interactions. Crit Rev Toxicol. 2012;42:854-876. 18. Hysek CM, Liechti ME. Effects of MDMA alone and after pretreatment with reboxetine, duloxetine, clonidine, carvedilol, and doxazosin on papillary light reflex. Psychopharmacology. 2012;224:363-376. 19. Peiro AM, Farre M, Roset PN, et al. Human pharmacology of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) after repeated doses taken 2 h apart. Psychopharmacology. 2013;225:883-893. 20. Hysek CM, Simmler LD, Nicola VG, et al. Duloxetine inhibits effects of MDMA (“ecstasy”) in vitro and in humans in a randomized placebo-controlled laboratory study. PLoS One. 2012;7:e36476. 21. Hall AP, Henry JA. Acute toxic effects of ecstasy (MDMA) and related compounds: overview of pathophysiology and clinical management. Br J Anaesth. 2006;96:678-685. 22. Parrott AC. Cortisol and 3,4-methylenedioxymethamphet amine: neurohormonal aspects of bioenergetic stress in ecstasy users. Neuropsychobiology. 2009;60:148-158. 23. Dumont GJH, Sweep FCGJ, van der Steen R, et al. Increased oxytocin concentrations and prosocial feelings in humans after ecstasy (3,4-methylenedioxymethamphetamine) administration. Soc Neurosci. 2009;4:359-366. 24. Bouso JC, Doblin R, Farre M, Alcazar MA, Gomez-Jarabo G. MDMA-assisted psychotherapy using low doses in a small sample of women with chronic posttraumatic stress disorder. J Psychoactive Drugs. 2008;40:225-236. 25. Grinspoon L, Bakalar JB. Can drugs be used to enhance the psychotherapeutic process? Am J Psychother. 1986;40:393-404. 26. Greer G, Tolbert R. Subjective reports of the effects of MDMA in a clinical setting. J Psychoactive Drugs. 1986;18: 319-327. 27. 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. 28. Mithoefer MC, Wagner MT, Mithoefer AT, 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. 29. Oehen P, Traber R, Widmer V, Schnyder U. A randomized, controlled pilot study of MDMA (3,4-methylenedioxymethamphetamine)assisted psychotherapy for treatment of post-traumatic stress disorder (PTSD). J Psychopharmacol. 2013;27:40-52. 30. Parrott AC. Is ecstasy MDMA? A review of the proportion of ecstasy tablets containing MDMA, their dosage levels, and the changing perceptions of purity. Psychopharmacology. 2004;173:234-241. 31. White CM. How MDMA’s pharmacology and pharmacokinetics drive desired effects and harms. J Clin Pharmacol. 2014;54:245-252.
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research-article2014
AOPXXX10.1177/1060028014532236Annals of PharmacotherapyWhite
Article
3,4-Methylenedioxymethamphetamine’s (MDMA’s) Impact on Posttraumatic Stress Disorder
Annals of Pharmacotherapy 1–8 © The Author(s) 2014 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028014532236 aop.sagepub.com
C. Michael White, PharmD, FCP, FCCP1
Abstract Objective: Review the current literature assessing the role of 3,4-methylenedioxymethamphetamine (MDMA) on posttraumatic stress disorder (PTSD). Data Sources: OVID MEDLINE search (1960-February 2014) using the terms MDMA, 3,4-methylenedioxymethamphetamine, Molly, and Ecstasy crossed with posttraumatic stress disorder with backwards citation tracking using references from procured articles. Study Selection and Data Extraction: English language studies assessing MDMA in patients with PTSD. Data Synthesis: Three randomized controlled trials (RCTs) were conducted along with follow-up open-label and extension evaluations. In the 3 RCTs, therapy with MDMA-assisted psychotherapy is promising, with reductions in PTSD rating scale scores (Clinician-Administered PTSD Scale, Severity of Symptoms Scale for PTSD Scale), although 2 of 3 trials did not show significant results, and all three had methodological limitations. The direction of effect for all trials was toward benefit in patients who were refractory to other PTSD therapies; the percentage reductions on rating scores ranged from 23% to 68%; and in 1 trial, the effect was sustained over a long period of time. MDMA ingestion without sustained psychotherapy over a 6- to 8-hour period is unlikely to be beneficial; trying to prolong the duration of effect with supplemental dosing is unlikely to provide additional benefits; and there are adverse effects on blood pressure and heart rate that should be appreciated. These studies used unadulterated MDMA with known and reproducible potency, which may not happen with street purchase of the product. Conclusions: MDMA-assisted psychotherapy may be an effective therapy in refractory PTSD but needs further evaluation to determine its place in contemporary therapy. Keywords PTSD, posttraumatic stress disorder, MDMA, Molly/Ecstasy, psychotherapy
Background Over their lifetime, 8% to 9% of the general population will develop posttraumatic stress disorder (PTSD), with women having twice the risk as men.1-3 However, the type of traumatic event greatly affects the risk of developing PTSD. The most common types of traumatic events resulting in PTSD include being held as a prisoner of war, rape, combat, physical traumatic assault, nonrape sexual assault, and serious accident/injury, with lifetime prevalence rates of 78%, 49%, 39%, 32%, 24%, and 17%, respectively.1-4 The trauma can be directly experienced (person in combat), personally witnessed (seeing someone beaten or murdered), or experienced vicariously through exposure of a loved one experiencing a traumatic event.1,5 PTSD chronically induces 3 types of symptom clusters: (1) intrusion symptoms (flashbacks, nightmares, and recurrent vivid images related to the event); (2) negative alterations in cognition/mood (inability to recall important details of the event or negative beliefs about self and situation); (3) avoidance and dissociation symptoms (avoiding situations
of events that trigger flashbacks and feeling emotionally disconnected from current events or other people); and (4) changes in arousal and reactivity (exaggerated startle response, excessive vigilance against danger, insomnia, and poor concentration).5 The Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Criterion A2 regarding the subjective reaction to the traumatic event, specifically intense fear, helplessness, or horror, has been eliminated because first responders and the military are trained to avoid this reaction.5 In this article, we will briefly review the current state of prescription pharmacotherapy and psychotherapy for PTSD, discuss the unique pharmacological effects of 3,4-methylenedioxymethamphetamine (MDMA) that could 1
University of Connecticut School of Pharmacy, Hartford, CT, USA
Corresponding Author: C. Michael White, Department of Pharmacy Practice, University of Connecticut School of Pharmacy, 69 N Eagleville Rd, Storrs, CT 062693092, USA. Email: [email protected]
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Table 1. Rating Scales Used in MDMA PTSD Studies.7,8 Rating Scale Severity of Symptoms Scale for PTSD (SSSPTSD) Clinician-Administered PTSD Scale (CAPS)
Components Two scales with each item in a scale rated as 0, 1, 2, or 3. Higher scores denote worse PTSD •• A 17-item Core Rating Scale (total score 0 to 51) 5 Items on reexperiencing symptoms 7 Items on avoidance symptoms 5 Items on arousal symptoms •• A 13-item supplementary scale (total score 0 to 39) Scale with each item rated on a 0 to 4 Likert scale for frequency (never to nightly or always) and intensity (none to extreme, overwhelming, or incapacitating). Higher scores denote worse PTSD with a score of >50 signifying moderate to severe disease •• 30-item CAPS-1 Scale 17 Items on symptoms of PTSD 8 Items on associated symptoms 5 Items on the impact of symptoms on societal functioning, improvement in PTSD symptoms since a previous assessment, overall response validity, and overall PTSD severity
Abbreviations: MDMA, 3,4-methylenedioxymethamphetamine; PTSD, posttraumatic stress disorder.
affect PTSD or the risk profile of MDMA, review in detail the clinical trials assessing MDMA in PTSD, and then briefly discuss issues associated with procuring and using MDMA outside of a clinical trial setting.
Current Pharmacotherapeutic and Psychotherapeutic Options for PTSD Several medications have been investigated for patients with PTSD, but only the selective serotonin reuptake inhibitors (SSRIs) paroxetine and sertraline have a Food and Drug Administration indication for the disorder.6 A systematic review of 37 randomized controlled trials (RCTs) comprising 5008 patients being treated for PTSD with prescription medication (SSRIs, venlafaxine, nefazodone, risperidone, topiramate, divalproex, tiagabine, prazosin, olanzapine, risperidone) was published in 2012. The main outcome measure was the impact on the Clinician Administered PTSD Scale (CAPS), the gold standard assessment scale, with reductions in score from baseline denoting improvements.6 A brief review of PTSD rating scales is given in Table 1.7,8 The SSRIs (citalopram, fluoxetine, paroxetine, and sertraline; −6.64 [95% CI = −9.11 to −4.16]) and venlafaxine (−8.11 [−12.30 to −3.92]) significantly affected CAPS score mean differences with moderate and minimal statistical heterogeneity (I2 statistics of 30%-50% and 15 (Table 1).7,8 Whereas the proposed sample size was 29 and was supposed to have patients randomized to 50, 75, 100, 125, and 150 mg or placebo, the study was reportedly terminated as a result of political pressure in Spain after only 6 patients were enrolled.24 Of these, 3 received 50 mg of MDMA, 1 received 75 mg MDMA, and 2 received placebo as a result of randomization. All underwent 7 psychotherapy sessions of 90 minutes’ duration, with only 1 session accompanied by MDMA or placebo. This psychotherapy session (session 4 of 8) began with MDMA ingestion and lasted for 6 hours, with patients resting for 2 additional hours after this psychotherapy session before being driven home. The authors did not conduct statistical analyses, but there were baseline and immediate postpsychotherapy data for all 6 participants (Table 2).24,27-29 The overall SSSPTSD scale scores were reduced by an average of 26.8% with MDMA plus psychotherapy and 10.1% with placebo plus psychotherapy, driven by larger reductions in the reexperiencing and avoidance subscales but similar reductions in the arousal and supplemental scales between the 2 groups.24 With only 1 patient receiving 75 mg of MDMA, assessing for a dose response effect is not prudent.
The second study by Mithoefer et al27 was a randomized, double-blind, placebo-controlled trial assessing the impact of 125-mg MDMA-assisted psychotherapy in refractory patients with PTSD (95% crime and 5% combat related trauma, 85% female, 100% Caucasian, 80% comorbid major depression). Patients underwent 11 regular nondrug psychotherapy sessions of 90 minutes’ duration along with 2 MDMA 125-mg or placebo sessions (sessions 5 and 11) of 8 to 10 hours followed by an overnight stay (zolpidem or lorazepam could be given for sleep that night if desired).27 Toward the end of the study, an amendment was approved allowing for a supplemental dose of MDMA of 62.5 mg or placebo in sessions 5 or 11 if investigators and participants agreed. The supplemental dose was administered to 4 participants in the MDMA group but no placebo patients, suggesting that participants and investigators were able to discern which group received MDMA and which received placebo. Overall, 23 patients were randomized (MDMA, n = 15; placebo, n = 8), but 2 MDMA patients dropped out (one for relapse of depression and another for unwillingness to travel), and another MDMA patient was judged not to be treatment resistant and did not receive MDMA therapy. The primary outcome was the impact of MDMA on the CAPS questionnaire taken at baseline, 4 days after each experimental session, and 2 months after the second experimental session. MDMA effects were perceptible at 45 to 75 minutes, peaked at 2 to 2.5 hours, and were gone by 4 to 5 hours in the nonsupplemented and 5 to 6 hours in the supplemented group. Mean CAPS scores were reduced at all follow-up times in both groups (group vs time interaction P < 0.001) but to a greater extent in the MDMA group versus the placebo group (group vs time interaction, P = 0.015; 67.8% reduction vs 25.8% reduction at 2 months after experimental session 2; Table 1).24,27-29 Investigators defined a clinically significant response as a >30% reduction in CAPS score, with 83.3% (10 of 12 patients) and 25.0% (2 of 8 patients) of MDMA and placebo patients achieving that level of benefit (P = 0.019; self-calculated, Primer of Statistics, Version 4.02, NY). There were no additional benefits on CAPS scores from using supplemental doses (group vs time interaction, P = 0.637).27 There were significantly greater maximum elevations in systolic (25.2 ± 13.7 vs 22.2 ± 15.3 mm Hg, P < 0.05) and diastolic blood pressures (14. 4 ± 6.5 vs 13.8 ± 7.5 mm Hg, P < 0.05), pulse (28.8 ± 11.5 vs 22.2 ± 13.7 bpm, P < 0.05), and temperature (0.5 ± 0.4 vs −0.7 ± 0.6, P < 0.05) versus baseline, but there were no significant differences by 6 hours after dosing. Investigators did not determine whether the use of supplemental MDMA dosing caused a different magnitude of hemodynamic effects versus standard doses alone.27 After the RCT, investigators established an open-label trial where patients receiving placebo could receive MDMA using the same protocol.27 In this open label MDMA
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23 (Three MDMA patients did not complete therapy)
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Patient Number
Treatment Regimen
MDMA given during two 8-hour experimental psychotherapy sessions to those previously given placebo MDMA 125 mg (n = 16) Comparison of longterm follow-up results of patients given MDMA versus 2 months post-MDMA therapy MDMA 25 mg + 12.5 mg MDMA or placebo given during three 2.5 hours later (n = 8-hour experimental 4); MDMA 125 mg + psychotherapy sessions 62.6 mg 2.5 hours later (n = 8)
MDMA 125 mg (n = 7)
MDMA 125 mg (n = 12); MDMA or placebo placebo (n = 8) given during two 8-hour experimental psychotherapy sessions
MDMA 50-75 mg MDMA or Placebo (n = 4); placebo (n = 2) given during one 6-hour experimental psychotherapy session
Treatment Groups
CAPS
CAPS
CAPS
CAPS
SSSPTSD
Primary Measure
High dose vs low dose •• CAPS baseline: 66.4 ± 13.6 vs 63.4 ± 7.9 •• CAPS session 2: 63.0 ± 17.8 vs 60.0 ± 6.8 •• CAPS session 3: 50.8 ± 19.7 vs 66.5 ± 7.6 Trend toward greater effects from higher-dose MDMA; 2-way ANOVA P = 0.066
2 Months post-MDMA vs 17-71 months Post-MDMA •• CAPS 2 months Post-MDMA: 23.7 ± 22.8 •• CAPS long-term post-MDMA: 24.6 ± 18.6 CAPS scores post-MDMA similar in the short and long term; P = 0.91
•• MDMA vs placebo SSSPTSD baseline: 40.0 ± 7.0 vs 44.5 ± 7.1 •• SSSPTSD posttherapy: 29.3 ± 8.7 vs 40.0 ± 1.4 •• SSSPTSD RE baseline: 12.8 ± 3.2 vs 12.5 ± 7.1 •• SSSPTSD RE post: 11.0 ± 4.5 vs 12.0 ± 1.4 •• SSSPTSD A baseline: 16.8 ± 2.6 vs 15.0 ± 2.8 •• SSSPTSD A post: 11.0 ± 4.1 vs 16.0 ± 0.0 •• SSSPTSD AI baseline: 10.5 ± 3.1 vs 14.0 ± 1.4 •• SSSPTSD AI post: 7.3 ± 1.7 vs 12.0 ± 0.0 •• SSSPTSD SS baseline: 24.3 ± 9.3 vs 25.0 ± 4.2 •• SSSPTSD SS post: 17.3 ± 8.7 vs 18.5 ± 13.4 P values not calculated because of small patient numbers, different MDMA doses administered, and unequal distribution between groups •• MDMA vs placebo CAPS baseline: 79.2 ± 6.6 vs 79.6 ± 8.1 •• CAPS session 1: 37.8 ± 8.4 vs 74.1 ± 10.3 •• CAPS session 2: 29.3 ± 6.5 vs 66.8 ± 8.0 •• CAPS 2 months post: 25.5 ± 7.7 vs 59.1 ± 9.4 Group vs time interaction showed greater improvements for MDMA than placebo (P = 0.015) •• Baseline vs MDMA CAPS baseline: 65.6 ± 24.4 •• CAPS 2 months post MDMA: 33.9 ± 12.8 CAPS scores significantly reduced with MDMA use versus baseline in patients previously receiving placebo; P < 0.05
Results (MDMA vs Placebo)
Abbreviations: MDMA, 3,4-methylenedioxymethamphetamine; PTSD, posttraumatic stress disorder; DB, double blind; PC, placebo control; SSSPTSD, Severity of Symptoms Scale for PTSD Scale; RE, re-experiencing; A, avoidance; AI, arousal increased; SS, supplemental scale; CAPS, Clinician-Administered PTSD Scale; OL, open label; AC, active control; R, randomized.
Oehen et al29 14 (2 Participants (2013), R, DB, AC dropped out of the trial, 1 per arm)
Mithoefer et al27 7 (2011) single arm, OL (OL study of Mithoefer et al27 above) Mithoefer et al28 19 (3 Participants did (2013), single arm, not complete the OL (OL extension long-term follow-up study of Mithoefer questionnaire) et al27 above)
Mithoefer et al27 (2011), R, DB, PC
Bouso et al (2008), R, DB, PC
Reference (Year), Trial Type
Table 2. Clinical Trials of MDMA in PTSD.24,27-29
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evaluation, 7 individuals participated, and all of them had evaluable data. Participants were eligible for the supplemental MDMA dose of 62.5 mg, and 4 individuals received it. MDMA reduced the mean CAPS score from the postplacebo baseline period to the 2-month post-MDMA open-label time period (65.6 ± 24.4 vs 33.9 ± 12.8, P < 0.05). All the participants had a clinically significant reduction of >30% versus the initial preplacebo baseline CAPS score. Investigators did not report whether supplemental doses affected results.27 All 19 patients utilizing MDMA (randomized trial + openlabel study) were asked to complete a long-term follow-up CAPS questionnaire.28 Of 19 patients, 16 completed the questionnaire (17 to 71 months after study completion), with the reasons for not completing the questionnaire reported as being lost to follow-up (n = 1), concern about triggering more symptoms (n = 1), and stressful family matters (n = 1). The one patient who did not want to trigger additional symptoms was reportedly the one who had the least benefit from MDMA during the initial study. The CAPS score at long-term followup in those completing the questionnaire approximated that seen 2 months after the experimental MDMA session 2 ended (23.7 ± 22.8 vs 24.6 ± 18.6, P = 0.91).28 The third study by Oehen et al29 was a randomized, double-blind comparison of psychotherapy assisted by low-dose MDMA (25 mg + 12.5-mg supplementary dose) versus high-dose MDMA therapy (125 mg + 62.5-mg supplementary dose).29 There were 3 experimental sessions where MDMA and psychotherapy was conducted over an 8-hour period (with an overnight stay) interspersed with 12 brief, nondrug psychotherapy sessions conducted weekly. CAPS scores were determined at baseline, 3 weeks after the second and third MDMA sessions, and 2 months and 1 year after the third MDMA session. Patients had to be refractory to other PTSD treatments. Of 12 individuals, 7 had experienced one or more evidence-based psychological therapies in the past (cognitive behavioral therapy, n = 3; exposure-based psychotherapy, n = 1; eye movement desensitization and reprocessing therapy, n = 1; and anxiety management therapy, n = 3). Also, 6 individuals had non–evidence-based psychotherapy such as insight-oriented therapy. Pharmacotherapy was reportedly used previously in patients but not specified, and individuals could not be on PTSD pharmacotherapy on entering the study. It was stated that many patients used multiple therapies in the past, so it was not possible for them to exactly identify each one. Chronic gabapentin was allowed for pain, and zolpidem and lorazepam could be used for sleep during experimental sessions. Two of 14 patients withdrew after receiving MDMA because of adverse events (1 in the low-dose and 1 in the high-dose MDMA groups) and had a different country of origin (Turkey and South Africa) than the others, who were all of European descent. The patient who dropped out while receiving low-dose MDMA reported dropping out because of feeling “overstressed by the process”; the reason for withdrawal in the other patient was not
specified. The remaining 12 patients (58% sexual assault and 0% war-related trauma, 83% female, 83% comorbid depression) had evaluable data. Of these, 8 patients received high-dose MDMA and 4 received low-dose MDMA. There was a non–statistically significant trend toward improved CAPS scores with high-dose versus Low-dose therapy (Table 2, 2-way ANOVA, P = 0.066).24,27-29 Patients on lowdose therapy had a higher CAPS score after the third session than they did at baseline, and the reductions in CAPS with high-dose therapy were most robust between experimental sessions 2 and 3 and were only modestly affected at the other time periods. The investigators stated that the low-dose MDMA group experienced spontaneous recall and relived traumatic events but without the positive and integrative effects of the high-dose MDMA state. They stated that using low-dose MDMA took more support from the therapists and was more trying for the participants than high-dose MDMA, but data to support this assertion was not provided. At 1 year of follow-up, CAPS scores were reportedly decreased by 24 points (35%) compared with baseline in the high-dose group, but statistical analysis was not conducted.29 There were no data at 1 year presented in the low-dose MDMA group. The investigators evaluated the impact on systolic and diastolic blood pressure, pulse, and temperature at baseline, maximum effects, and 8 hours, but statistical analysis was not completed.29 The maximum values for each parameter were higher than at baseline, with greater increases in highdose therapy versus Low-dose therapy for every parameter except temperature, which was similarly increased. The maximal increases in systolic blood pressure (134.3 ± 17.3 vs 160.1 ± 21.1 mm Hg) and pulse rate (79.7 ± 7.4 vs 98.5 ± 13.3 bpm) were especially marked in the high-dose MDMA group versus baseline. However, all elevations resolved by the 8-hour final evaluation.29 At the end of the RCT, the 4 individuals in the low-dose MDMA group were given high-dose MDMA in the openlabel phase, with results provided at 1 year follow-up. There was a 35-point decrease (52%) in the CAPS score in these 4 patients versus baseline (no statistical analysis conducted).29 For the 3 patients originally included in the high-dose MDMA group who did not exhibit much response from MDMA therapy, the clinicians were allowed to give them additional high-dose MDMA sessions at the conclusion of the RCT.29 The exact dose used was determined by clinical judgment, but the mean CAPS scores were only reduced by 0.3 points.
Issues in Acquiring and Using MDMA In 1985, the Drug Enforcement Agency labeled MDMA a schedule I drug (no approved medical use, high abuse potential, and illegal to possess), and the manufacture, transport, and sale of MDMA products are illegal.30 This illegality and the lack of regulation and oversight results in
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White MDMA products that vary widely in potency, can contain other drugs of abuse without disclosure to the buyers, or can be manufactured in unsanitary settings.31 From the early 1980s to the late 1990s, MDMA products went from being rarely contaminated with other substances to having a majority of tablets not containing MDMA but instead being composed of other amphetamine and psychedelic substances. Over the past several years, up to 90% of tablets sold as MDMA contain MDMA but may still be adulterated with other substances; also, the dosage of MDMA per tablet varied widely, from 20 to 150 mg.31 The main adverse effects of MDMA include cardiac events (myocardial infarction, stroke, and arrhythmia), hyponatremia, hyperpyrexia, rhabdomyolysis, and disseminated intravascular coagulopathy.31 Vigorous activity accentuates the pharmacological effects of MDMA and, therefore, the adverse event potential. MDMA use has been associated with neurotoxicity and hepatotoxicity. Although people have euphoric effects within a few hours of dosing, they have a prolonged depressed mood for several days thereafter arising from depletion of serotonin stores. Patients with coronary disease, uncontrolled hypertension, arrhythmias or genetic predisposition to arrhythmias, hyperpyrexia, liver cirrhosis, neurotoxicity, and hyponatremia should likely avoid MDMA therapy.31 Even if people could acquire a reliable and stable supply of MDMA and replicate the study procedures with methodological safeguards, the possession of MDMA by mental health professionals or patients is illegal and could result in arrest and/or imprisonment.
Conclusions MDMA-assisted psychotherapy is a promising therapy for refractory PTSD.24-29 The benefits may be appreciable and may be sustained over the longer term, but these clinical trials are preliminary, had methodological weaknesses, and are not definitive.24,27-29 It appears that 125 mg is an effective dose, mostly affecting reexperiencing and avoidance, and supplemental MDMA dosing is not beneficial.24,27 If patients do not respond to MDMA therapy by the end of the third assisted psychotherapy, additional MDMA sessions are unlikely to help.27,29 These results may not be applicable to all ethnic groups and for all PTSD causes. The only 2 withdrawals in the Oehen trial were in non-Europeans; the Mithoefer trial was conducted solely in Caucasians; and the ethnicity in the Bouso trial was not reported, but it was conducted in Spain.27,29 The current trials focus heavily on patients with sexual assault (in childhood or adulthood), and there is virtually no clinical trial experience in those with war-related causes of PTSD.24,27-29 Given the complexity of the protocol with 6- to 8-hour therapy sessions, therapists of both genders being present, and overnight stays, MDMAassisted psychotherapy may be cost prohibitive for some
people.24,27-29 Although MDMA assisted psychotherapy may be better than the same type of psychotherapy applied without MDMA, whether it would be superior to combined standard-of-care psychotherapy with SSRI therapy is unknown and should be the focus of a subsequent clinical trial. Anecdotally in the 3 trials, some patients originally unable to work were able to begin working again after MDMAassisted pharmacotherapy, but this was not a prespecified aim.24,27-29 Unlike the current pilot evidence, any follow-up study should use an intention-to-treat analysis, so that withdrawals are better captured and accounted for. The investigators should also have the freedom to analyze and report their results without the involvement of MAPS personnel. Patients who are currently receiving SSRIs, which are known to block much of the pharmacological effects of MDMA, might experience lackluster results such as those seen in the lower-dose MDMA group in the trial by Oehen et al29 and others.20 In the clinical trials for MDMA in PTSD, patients tapered off psychopharmacological therapy before they underwent study procedures, but they did not report on the impact of doing this on the majority of their patients with comorbid depression.24,27-29 There are adverse hemodynamic effects that might make MDMA use inappropriate in certain patients.27,29 Patients with uncontrolled hypertension, arrhythmias, coronary artery disease, or stroke might have untoward adverse effects from the elevations in blood pressure and pulse rate.31 MDMA and its metabolites are CYP and COMT metabolized, and MDMA is also a CYP2D6 inhibitor, so people with genetic polymorphisms or who are on interacting medications might be at risk of unpredictable effects.17,21 It should be noted that MDMA use gives people the feeling of having additional energy, but the combination of exercise and MDMA has been shown to accentuate the impact of therapy on blood pressure, heart rate, and the release of neurochemicals and hormones that can lead to adverse events.17 In the 3 PTSD trials, the researchers were very careful to monitor hemodynamics and temperature and to give patients instructions to rest during the 8-hour period, use relaxing music, and undergo introspection.24,27-29 MDMA-facilitated psychotherapy should be further studied for patients with PTSD but cannot be recommended for clinical use at the present time because of safety considerations, legal ramifications of its schedule I drug status, and the need for additional studies to assess the balance of benefits and harms.30,31 Declaration of Conflicting Interests The author declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author received no financial support for the research, authorship, and/or publication of this article.
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