MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study

Post-traumatic stress disorder (PTSD) presents a major public health problem for which currently available treatments are modestly effective. We report the findings of a randomized, double-blind, placebo-controlled, multi-site phase 3 clinical trial (NCT03537014) to test the efficacy and safety of 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy for the treatment of patients with severe PTSD, including those with common comorbidities such as dissociation, depression, a history of alcohol and substance use disorders, and childhood trauma. After psychiatric medication washout, participants (n = 90) were randomized 1:1 to receive manualized therapy with MDMA or with placebo, combined with three preparatory and nine integrative therapy sessions. PTSD symptoms, measured with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5, the primary endpoint), and functional impairment, measured with the Sheehan Disability Scale (SDS, the secondary endpoint) were assessed at baseline and at 2 months after the last experimental session. Adverse events and suicidality were tracked throughout the study. MDMA was found to induce significant and robust attenuation in CAPS-5 score compared with placebo (P < 0.0001, d = 0.91) and to significantly decrease the SDS total score (P = 0.0116, d = 0.43). The mean change in CAPS-5 scores in participants completing treatment was −24.4 (s.d. 11.6) in the MDMA group and −13.9 (s.d. 11.5) in the placebo group. MDMA did not induce adverse events of abuse potential, suicidality or QT prolongation. These data indicate that, compared with manualized therapy with inactive placebo, MDMA-assisted therapy is highly efficacious in individuals with severe PTSD, and treatment is safe and well-tolerated, even in those with comorbidities. We conclude that MDMA-assisted therapy represents a potential breakthrough treatment that merits expedited clinical evaluation.

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

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

Gender differences in the subjective effects of MDMA

Rationale: 3,4-Methylenedioxymethamphetamine (MDMA) mainly releases serotonin (5-HT) and is contained in the recreational drug Ecstasy. 5-HT is known to play an important role in mood and anxiety disorders, for which there is a female preponderance. To date, there are no systematic data on gender differences in the subjective effects of MDMA. Objectives: The present work analyzed the pooled data from three controlled studies on the psychological and physiological effects of MDMA in healthy volunteers with no or minimal MDMA experience. A particular focus of the analyses were possible gender differences. Methods: A total of 74 subjects (54 male, 20 female) participated in all three studies. MDMA in oral doses ranging from 70–150 mg (1.35–1.8 mg/kg) was administered under double-blind placebo-controlled conditions. Subjective peak changes were assessed by standardized psychometric rating scales. Physiological measures were blood pressure, heart rate, and peripheral body temperature. Adverse drug effects were assessed during the experimental session and after 24 h. Results: Psychoactive effects of MDMA were more intense in women than in men. Women especially had higher scores for MDMA-induced perceptual changes, thought disturbances, and fear of loss of body control. The dose of MDMA positively correlated with the intensity of perceptual changes in women. Acute adverse effects and sequelae were also more frequent in female than in male subjects. In contrast, men showed higher increases in blood pressure than woman. Conclusions: The fact that equal doses of MDMA per kilogram body weight produce stronger responses in women compared to men is consistent with an increased susceptibility of women to the 5-HT-releasing effects of MDMA. Our results also indicate that increasing doses of MDMA produce more hallucinogen-like perceptual alterations, particularly in women.

Through the Gateway of the Heart: Accounts of Experiences with MDMA and other Empathogenic Substances

MDMA, or as it is commonly known, “ecstasy,” has a pardoxical double role in contemporary society. As the party-drug ecstasy, it is consumed by tens (perhaps hundreds) of thousands of people at “rave” dance parties in the United States, Europe, and the Far East. In its other role as a promising adjunct to psychotherapy, MDMA is currently being researched as a treatment for many conditions, including PTSD, obsessive-compulsive disorder, and interpersonal anxiety. This book, originally published in 1985 before MDMA became illegal, is a compilation of experiences conducted in supportive and/or therapeutic settings. The vignettes are not part of a formal research study, and there is no control group. These accounts illustrate the value and potential of MDMA for generating insight, facilitating empathic communication, and supporting spiritual practice. Although the use of MDMA remains illegal (except in the limited context of research), the editors of this book, like many professionals in the field of psychotherapy, believe that a fresh look at this very promising substance is warranted.

Deconstructing Ecstasy: The Politics Of Mdma Research

What is Ecstasy? Defined by the New Webster’s Dictionary as a state of intense overpowering emotion, a condition of exultation or mental rapture induced by beauty, music, artistic creation or the contemplation of the divine, ecstasy derives etymologically from the ancient Greek ekstasis, which means flight of the soul from the body. The anthropologist, Mircea Eliade, who explored the roots of religious experience in his book Shamanism: Archaic Techniques of Ecstasy, has described the function of this intense state of mind among aboriginal peoples. Select individuals are called to become shamans, a role specializing in inducing ecstatic states of trance where the soul is believed to leave the body and ascend to the sky or descend to the underworld. The shaman is thus considered a “technician of the sacred”, having been initiated through a process of isolation, ritual solitude, suffering and the imminence of death. Such initiation into the function of ecstatic states of consciousness, always accompanied by comprehensive tutelage from tribal elders, allows the shaman to assume for his tribal group the vital role of intermediary, or conduit, between the profane world of everyday existence and the sacred domains of alternative reality (Eliade, 1951; Schultes and Hofmann, 1992).

Acid Test: LSD, Ecstasy, and the Power to Heal

With the F.D.A. agreeing to new trials to test MDMA (better known as Ecstasy) as a treatment for PTSD—which, if approved, could be available as a drug by 2021—Acid Test is leading the charge in an evolving conversation about psychedelic drugs. Despite their current illegality, many Americans are already familiar with their effects. Yet while LSD and MDMA have proven extraordinarily effective in treating anxiety disorders such as PTSD, they still remain off-limits to the millions who might benefit from them. Through the stories of three very different men, award-winning journalist Tom Shroder covers the drugs’ roller-coaster history from their initial reception in the 1950s to the negative stereotypes that persist today. At a moment when popular opinion is rethinking the potential benefits of some illegal drugs, and with new research coming out every day, Acid Test is a fascinating and informative must-read.

PiHKAL

Alexander (better known as “Sasha”) and Ann Shulgin’s PiHKAL: A Chemical Love Story has become a foundational work in the genre and was the first book to fully impart the how-to chemistry, and convey the effects, of many of the entheogenic drugs that are currently being studied and used to heal trauma and deal with death. An acronym for “Phenethylamines I Have Known and Loved”, the book spans autobiography, organic chemistry, politics, ethnobotany, and psychopharmacology, and the cultural impact is likely to be profound for decades to come, as it has already. PiHKAL is divided into two parts, the first of which is a fictionalized autobiographical ‘novel’ – the main fiction is that it is fiction. This first half of the book is The Love Story, about two people named Shura and Alice who fall in love, though one of them is already in love with someone else. This love triangle is a painful ordeal they must go through, and that process unfolds before the reader with grace and great insight into human nature. Shura is a brilliant chemist who has dedicated his career to making psychoactive drugs, in the story they go through many experiences with the psychedelic compounds that Shura has discovered and has made in his lab, all of which have been bioassayed himself. The reader will find themselves going on this journey with them, experiencing what they experienced, both in their hearts and in the psychedelic journeys they have. The second half of PiHKAL is called The Chemical Story, and it contains detailed instructions for, and effects of, the synthesis of 179 psychedelic phenethylamines which were mostly discovered by Shulgin himself. For each substance there is information on its synthesis, suggested effective dosage, duration, and detailed commentary on the subjective effects that were experienced. This book appeals to adults of all ages and cultures, and to the psychedelically experienced and inexperienced alike.

TiHKAL

TiHKAL: The Continuation is the sequel to PiHKAL: A Chemical Love Story but can stand alone to any reader. Where PiHKAL focuses on a class of compounds called phenethylamines, TiHKAL is written about a family of psychoactive drugs known as tryptamines with TiHKAL being an acronym for “Tryptamines I Have Known and Loved”. Like its predecessor PiHKAL, it is divided into two parts. The first part of the book begins with the story of Alice and Shura, a fictionalized autobiography, which picks up where the similar section of PiHKAL left off. The book opens with the story about the DEA raid that occurred a few years after the publication of their first book, PiHKAL. It’s a window into the DEA, the institutional aspect and human side of it as well, and the price that Shura and Alice pay for doing what they do, including exercising their first amendment rights. It then continues with a collection of essays on topics ranging from psychotherapy and the Jungian mind, to the prevalence of DMT in nature, ayahuasca, the War on Drugs, and even the Big Bang. It is a blend of travel, botanical facts, scientific speculation, psychological and political commentary. It is fascinating getting to know the mind of the man behind the compounds – his thoughts on science, technology, law, and society. And the mind of the woman who brought his work and their story into the light of the world. The second part of TiHKAL is “The Chemistry Continues”. It is a detailed manual for 55 psychedelic compounds (many discovered by Shulgin himself). For each compound there is information on synthesis, effective dosage, duration of effects, and commentary on the subjective effects that were experienced. The Shulgins’ two big books span autobiography, organic chemistry, politics, ethnobotany and psychopharmacology and the cultural impact of these works has been profound and will continue to be so in the future.

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