Michael C. Mithoefer

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

Case reports indicate that psychiatrists administered ±3,4-methylenedioxymethamphetamine (MDMA) as a catalyst to psychotherapy before recreational use of MDMA as ‘Ecstasy’ resulted in its criminalization in 1985. Over two decades later, this study is the first completed clinical trial evaluating MDMA as a therapeutic adjunct. Twenty patients with chronic posttraumatic stress disorder, refractory to both psychotherapy and psychopharmacology, were randomly assigned to psychotherapy with concomitant active drug (n = 12) or inactive placebo (n = 8) administered during two 8-h experimental psychotherapy sessions. Both groups received preparatory and follow-up non-drug psychotherapy. The primary outcome measure was the Clinician-Administered PTSD Scale, administered at baseline, 4 days after each experimental session, and 2 months after the second session. Neurocognitive testing, blood pressure, and temperature monitoring were performed. After 2-month follow-up, placebo subjects were offered the option to re-enroll in the experimental procedure with open-label MDMA. Decrease in Clinician-Administered PTSD Scale scores from baseline was significantly greater for the group that received MDMA than for the placebo group at all three time points after baseline. The rate of clinical response was 10/12 (83%) in the active treatment group versus 2/8 (25%) in the placebo group. There were no drug-related serious adverse events, adverse neurocognitive effects or clinically significant blood pressure increases. MDMA-assisted psychotherapy can be administered to posttraumatic stress disorder patients without evidence of harm, and it may be useful in patients refractory to other treatments.

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:

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.

Novel psychopharmacological therapies for psychiatric disorders: psilocybin and MDMA

4-phosphorloxy-N,N-dimethyltryptamine (psilocybin) and methylenedioxymethamfetamine (MDMA), best known for their illegal use as psychedelic drugs, are showing promise as therapeutics in a resurgence of clinical research during the past 10 years. Psilocybin is being tested for alcoholism, smoking cessation, and in patients with advanced cancer with anxiety. MDMA is showing encouraging results as a treatment for refractory post-traumatic stress disorder, social anxiety in autistic adults, and anxiety associated with a life-threatening illness. Both drugs are studied as adjuncts or catalysts to psychotherapy, rather than as stand-alone drug treatments. This model of drug-assisted psychotherapy is a possible alternative to existing pharmacological and psychological treatments in psychiatry. Further research is needed to fully assess the potential of these compounds in the management of these common disorders that are difficult to treat with existing methods.

A reconsideration and response to Parrott AC (2013) “Human psychobiology of MDMA or ‘Ecstasy’: an overview of 25 years of empirical research”

Parrott recently published a review of literature on MDMA/ecstasy. This commentary is a response to the content and tenor of his review, which mischaracterizes the literature through misstatement and omission of contrary findings, and fails to address the central controversies in the literature. The review makes several erroneous statements concerning MDMA‐assisted psychotherapy, such as incorrect statements about research design and other statements that are baseless or contradicted by the literature. Though it critiques an attempt by other authors to characterize the risks of MDMA, the review fails to produce a competing model of risk assessment, and does not discuss potential benefits. Parrott does not represent an even‐handed review of the literature, but instead recites dated misconceptions about neurotoxicity concerns involving the recreational drug ecstasy, which do not relate directly to the use of pure MDMA in a therapeutic setting. Unchallenged, Parrotts report may deter researchers from further investigating an innovative treatment that in early clinical trials has demonstrated lasting benefits for people with chronic, treatment‐resistant post‐traumatic stress disorder. Copyright

Therapeutic effect of increased openness: Investigating mechanism of action in MDMA-assisted psychotherapy

A growing body of research suggests that traumatic events lead to persisting personality change characterized by increased neuroticism. Relevantly, enduring improvements in Post-Traumatic Stress Disorder (PTSD) symptoms have been found in response to 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy. There is evidence that lasting changes in the personality feature of “openness” occur in response to hallucinogens, and that this may potentially act as a therapeutic mechanism of change. The present study investigated whether heightened Openness and decreased Neuroticism served as a mechanism of change within a randomized trial of MDMA-assisted psychotherapy for chronic, treatment-resistant PTSD. The Clinician-Administered PTSD Scale (CAPS) Global Scores and NEO PI-R Personality Inventory (NEO) Openness and Neuroticism Scales served as outcome measures. Results indicated that changes in Openness but not Neuroticism played a moderating role in the relationship between reduced PTSD symptoms and MDMA treatment. Following MDMA-assisted psychotherapy, increased Openness and decreased Neuroticism when comparing baseline personality traits with long-term follow-up traits also were found. These preliminary findings suggest that the effect of MDMA-assisted psychotherapy extends beyond specific PTSD symptomatology and fundamentally alters personality structure, resulting in long-term persisting personality change. Results are discussed in terms of possible mechanisms of psychotherapeutic change.

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

BACKGROUND Post-traumatic stress disorder (PTSD) is prevalent in military personnel and first responders, many of whom do not respond to currently available treatments. This study aimed to assess the efficacy and safety of 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for treating chronic PTSD in this population. METHODS We did a randomised, double-blind, dose-response, phase 2 trial at an outpatient psychiatric clinic in the USA. We included service personnel who were 18 years or older, with chronic PTSD duration of 6 months or more, and who had a Clinician-Administered PTSD Scale (CAPS-IV) total score of 50 or greater. Using a web-based randomisation system, we randomly assigned participants (1:1:2) to three different dose groups of MDMA plus psychotherapy: 30 mg (active control), 75 mg, or 125 mg. We masked investigators, independent outcome raters, and participants until after the primary endpoint. MDMA was administered orally in two 8-h sessions with concomitant manualised psychotherapy. The primary outcome was mean change in CAPS-IV total score from baseline to 1 month after the second experimental session. Participants in the 30 mg and 75 mg groups subsequently underwent three 100-125 mg MDMA-assisted psychotherapy sessions in an open-label crossover, and all participants were assessed 12 months after the last MDMA session. Safety was monitored through adverse events, spontaneously reported expected reactions, vital signs, and suicidal ideation and behaviour. This study is registered with ClinicalTrials.gov, number NCT01211405. FINDINGS Between Nov 10, 2010, and Jan 29, 2015, 26 veterans and first responders met eligibility criteria and were randomly assigned to receive 30 mg (n=7), 75 mg (n=7), or 125 mg (n=12) of MDMA plus psychotherapy. At the primary endpoint, the 75 mg and 125 mg groups had significantly greater decreases in PTSD symptom severity (mean change CAPS-IV total scores of -58·3 [SD 9·8] and -44·3 [28·7]; p=0·001) than the 30 mg group (-11·4 [12·7]). Compared with the 30 mg group, Cohens d effect sizes were large: 2·8 (95% CI 1·19-4·39) for the 75 mg group and 1·1 (0·04-2·08) for the 125 mg group. In the open-label crossover with full-dose MDMA (100-125 mg), PTSD symptom severity significantly decreased in the group that had previously received 30 mg (p=0·01), whereas no further significant decreases were observed in the group that previously achieved a large response after 75 mg doses in the blinded segment (p=0·81). PTSD symptoms were significantly reduced at the 12-month follow-up compared with baseline after all groups had full-dose MDMA (mean CAPS-IV total score of 38·8 [SD 28·1] vs 87·1 [16·1]; p<0·0001). 85 adverse events were reported by 20 participants. Of these adverse events, four (5%) were serious: three were deemed unrelated and one possibly related to study drug treatment. INTERPRETATION Active doses (75 mg and 125 mg) of MDMA with adjunctive psychotherapy in a controlled setting were effective and well tolerated in reducing PTSD symptoms in veterans and first responders. FUNDING Multidisciplinary Association for Psychedelic Studies.

Progress and promise for the MDMA drug development program

Pharmacotherapy is often used to target symptoms of posttraumatic stress disorder (PTSD), but does not provide definitive treatment, and side effects of daily medication are often problematic. Trauma-focused psychotherapies are more likely than drug treatment to achieve PTSD remission, but have high dropout rates and ineffective for a large percentage of patients. Therefore, research into drugs that might increase the effectiveness of psychotherapy is a logical avenue of investigation. The most promising drug studied as a catalyst to psychotherapy for PTSD thus far is 3,4-methylenedioxymethamphetamine (MDMA), commonly known as the recreational drug “Ecstasy.” MDMA stimulates the release of hormones and neurochemicals that affect key brain areas for emotion and memory processing. A series of recently completed phase 2 clinical trials of MDMA-assisted psychotherapy for treatment of PTSD show favorable safety outcomes and large effect sizes that warrant expansion into multi-site phase 3 trials, set to commence in 2018. The nonprofit sponsor of the MDMA drug development program, the Multidisciplinary Association for Psychedelic Studies (MAPS), is supporting these trials to explore whether MDMA, administered on only a few occasions, can increase the effectiveness of psychotherapy. Brain imaging techniques and animal models of fear extinction are elucidating neural mechanisms underlying the robust effects of MDMA on psychological processing; however, much remains to be learned about the complexities of MDMA effects as well as the complexities of PTSD itself.

MDMA-assisted psychotherapy for PTSD: Are memory reconsolidation and fear extinction underlying mechanisms?

ABSTRACT MDMA‐assisted psychotherapy for treatment of PTSD has recently progressed to Phase 3 clinical trials and received Breakthrough Therapy designation by the FDA. MDMA used as an adjunct during psychotherapy sessions has demonstrated effectiveness and acceptable safety in reducing PTSD symptoms in Phase 2 trials, with durable remission of PTSD diagnosis in 68% of participants. The underlying psychological and neurological mechanisms for the robust effects in mitigating PTSD are being investigated in animal models and in studies of healthy volunteers. This review explores the potential role of memory reconsolidation and fear extinction during MDMA‐assisted psychotherapy. MDMA enhances release of monoamines (serotonin, norepinephrine, dopamine), hormones (oxytocin, cortisol), and other downstream signaling molecules (BDNF) to dynamically modulate emotional memory circuits. By reducing activation in brain regions implicated in the expression of fear‐ and anxiety‐related behaviors, namely the amygdala and insula, and increasing connectivity between the amygdala and hippocampus, MDMA may allow for reprocessing of traumatic memories and emotional engagement with therapeutic processes. Based on the pharmacology of MDMA and the available translational literature of memory reconsolidation, fear learning, and PTSD, this review suggests a neurobiological rationale to explain, at least in part, the large effect sizes demonstrated for MDMA in treating PTSD. HIGHLIGHTSMDMA‐assisted psychotherapy for treatment of posttraumatic stress disorder received Breakthrough Therapy designation by FDA after six Phase 2 trials demonstrated promising safety and efficacy results.MDMA stimulates release of monoamines, hormones, and signaling molecules that modulate emotional memory circuits engaged in reprocessing of traumatic memories.Fear extinction and memory reconsolidation could possibly be mechanisms underlying the beneficial outcomes of MDMA‐assisted psychotherapy for reducing PTSD symptoms.

Response to: Parrott AC, Buchanan T, Heffernan TM, Scholey A, Ling J, Rodgers J (2003) Parkinson's disorder, psychomotor problems and dopaminergic neurotoxicity in recreational ecstasy/MDMA users. Psychopharmacology 167(4):449-450.

To the Editors; In their recent letter, Parrott and colleagues discussed the human implications of findings of dopaminergic neurotoxicity in non-human primates after repeated doses of MDMA (three injections of 2 mg/ kg within 6 h) (Ricaurte et al. 2002). Parrott and colleagues are concerned that like the known neurotoxin MPTP, MDMA might only produce observable effects in a minority of ecstasy users. They supported their concerns by citing a survey conducted over the internet that yielded reports of tremors and twitches in 20% of 282 ecstasy users. However, scientists disagree on the human implications of Ricaurte’s findings, and an examination of the literature fails to support a link between ecstasy use and dopaminergic neurotoxicity or motor problems (Holden 2002). The MDMA dose regimen used by Ricaurte and colleagues produced 20% mortality in their animals, a figure that far exceeds the estimated percentage of deaths in ecstasy users (Gore 1999; Gill et al. 2003; Henry and Rella 2001). An additional 20% of their test animals were not administered the third injection due to obvious signs of behavioural toxicity. Clearly, the dose regimen employed in this study was not analogous to common patterns of ecstasy use. At present, two studies of cerebrospinal fluid and two imaging studies in heavy ecstasy users, and one postmortem examination of brain tissue from a heavy ecstasy user have all failed to find evidence for ecstasy-related dopamine neurotoxicity (Ricaurte et al. 1988, 1990; McCann et al. 1994, 1999; Semple et al. 1999; Kish 2000; Reneman et al. 2002), although one of these imaging studies found a relationship between amphetamine use and reduced striatal dopamine (Reneman et al. 2002). As Parrott and colleagues stated themselves, any research testing hypotheses concerning ecstasy use and dopaminergic neurotoxicity must take into account use of amphetamine and other psychostimulants. Parrott and colleagues presented data from their online survey of ecstasy users and described anecdotal accounts of movement problems in ecstasy users (Parrott et al. 2002). Participants reporting motor problems in this and other studies (Parrott and Lasky 1998; Rodgers 2000) did not undergo clinical assessments of psychomotor function, and, in one case, reports were elicited in response to a specific question (Rodgers 2000). Responses from ecstasy users were not compared with comparable samples, such as polydrug users with no reported ecstasy use. Subjects in this study also generally reported fewer ecstasy episodes than the aforementioned imaging studies, suggesting that underlying dose-related dopaminergic neurotoxicity must be discounted as a causal mechanism. In contrast with these findings, a survey of 500 ecstasy users failed to report a significant number of complaints of psychomotor problems after ecstasy use (Cohen et al. 1995). The lack of independent verification of symptoms is particularly important, since the links between symptom reporting and results of objective measures are not strong. Studies of memory and executive function in ecstasy users failed to find relationships between self-reported cognitive difficulties attributed to ecstasy use and performance on tests of spatial memory, verbal memory and executive function (Rodgers 2000; Fox et al. 2001; Heffernan 2001, study 2). In the study conducted by Fox and colleagues, lifetime ecstasy consumption was a better predictor of performance on measures of spatial memory H. R. Sumnall ()) Centre for Public Health, Liverpool John Moores University, 70 Great Crosshall Street, Liverpool, L3 2AB, UK e-mail: h.sumnall@livjm.ac.uk