'Ecstasy' shows promise for post-traumatic stress treatment

Psychotherapy and medication proves helpful for chronic sufferers

May 30, 2019

Science Daily/University of British Columbia Okanagan campus

An international study has shown that MDMA, also known as ecstasy, may be a valuable tool for treating post-traumatic stress disorder (PTSD). The study demonstrated substantial improvements in individuals who had not responded to prior treatments. This is also, he adds, the most comprehensive evaluation of the safety and effectiveness of MDMA-assisted psychotherapy for PTSD.

An international study involving researchers from UBC Okanagan has shown that MDMA, also known as ecstasy, may be a valuable tool for treating post-traumatic stress disorder (PTSD).

Published recently in Psychopharmacology, the study demonstrated substantial improvements in individuals who had not responded to prior treatments, explains UBCO Associate Professor of psychology Zach Walsh. This is also, he adds, the most comprehensive evaluation of the safety and effectiveness of MDMA-assisted psychotherapy for PTSD.

"PTSD symptoms decreased after one session of MDMA together with psychotherapy," says Walsh, study co-author. He adds that 54 per cent of participants no longer met PTSD criteria after two sessions and that there was also improvement in their symptoms of depression.

The response of participants to MDMA-assisted psychotherapy was compared to those who received small doses or non-drug psychotherapy.

"These findings are promising and indicate the needed for larger studies," says Walsh. "Too many people with PTSD struggle to find effective treatment, and use of MDMA in a supportive environment with trained mental health professionals could be an important addition to our treatment options."

Ecstasy, also known as Molly, is the nickname for MDMA -- a synthetic drug made from a combination of methylenedioxy-methamphetamine. It is a controlled, illegal drug in Canada classified as a stimulant with hallucinogenic properties.

Walsh, as well as researchers from the United States, Switzerland and Israel, examined the results from six clinical trials, involving 103 people. Trial participants included men and women with chronic, treatment-resistant PTSD from a wide variety of causes.

Based on these results, the US Food and Drug Administration granted breakthrough therapy designation to MDMA-assisted psychotherapy for PTSD, acknowledging that it "may demonstrate substantial improvement over existing therapies" and agreeing to expedite its development and review.

The first of two more in-depth clinical trials of MDMA-assisted psychotherapy for PTSD began enrolling participants in November 2018, and aims to have 100-150 volunteers across 15 sites in the US, Canada and Israel. The second trial will take place after an interim analysis of the data from the first trial, and will enrol an additional 100-150 participants. European trials are planned to start in the near future.

Nearly four per cent of all people worldwide will suffer from PTSD during their lifetime. PTSD can be a debilitating disorder, with symptoms including intrusive thoughts and memories, negative effects on thinking and mood, depression, hyperarousal and reactivity, and avoidance. People with PTSD can experience much lower quality of life and relationships, related mental health conditions and suicidal tendencies.

https://www.sciencedaily.com/releases/2019/05/190530101215.htm

Psychedelic drug MDMA may reawaken 'critical period' in brain to help treat PTSD

April 4, 2019

Science Daily/Johns Hopkins Medicine

Johns Hopkins neuroscientists have found that the psychedelic drug MDMA reopens a kind of window, called a "critical period," when the brain is sensitive to learning the reward value of social behaviors. The findings, reported April 3 in Nature, may explain why MDMA may be helpful in treating people with post-traumatic stress disorder (PTSD).

Critical periods were first described in the 1930s in snow geese. About 24 hours after a gosling hatches, if mother goose is nowhere to be found, the hatchling will bond with an object, including non-living ones. Yet, if mother goose disappears 48 hours after her gosling hatches, the critical period is over, and the hatchling won't bond to an object.

There is evidence for critical periods that smooth the way for development of language, touch and vision.

For the current study, neuroscientist Gül Dölen says, "We wanted to know if there was a critical period for learning social reward behaviors, and if so could we reopen it using MDMA, since this drug is well-known to have prosocial effects."

Dölen and her team studied groups of mice in enclosures with different bedding. They put several mice together in one enclosure with one type of bedding for 24 hours and, in the next 24 hours, put the same mice by themselves in another enclosure with a different type of bedding. The mice began to associate certain types of bedding with isolation or companionship. Then, they let the mice wander between enclosures with the two types of bedding and tracked how long the mice spent in each enclosure. The more time the mice spent in the bedding linked to their companions indicated more social reward learning.

"It's why people gather around the water cooler," says Dölen, assistant professor of neuroscience at the Johns Hopkins University School of Medicine. People are conditioned to know that the water cooler is an optimal place to chitchat with companions.

In their experiments, Dölen and her colleagues found that the critical period for social reward learning in mice is around puberty and wanes once they become mature adults. To determine if they could reopen the critical period, the scientists gave MDMA to mature mice, waited 48 hours for the drug to be washed out of their system, and observed how the mice explored their enclosure and behaved with other mice in the enclosure. Following the treatment with MDMA, most of the animals responded to social interactions the same way as juveniles, by forming a positive association between social interactions and the bedding. This effect lasted for at least two weeks after the MDMA treatment, and it was not observed in mice given saline injections.

"This suggests that we've reopened a critical period in mice, giving them the ability to learn social reward behaviors at a time when they are less inclined to engage in these behaviors," says Dölen.

Dölen and her postdoctoral student and first author of the current study, Romain Nardou, also observed that MDMA works to reopen the critical period only if the drug is given to mice when they are with other mice, not if it is given to mice while they are alone. This suggests that reopening the critical period using MDMA may depend on whether the animals are in a social setting, say the scientists.

The mice maintained their ability to learn the rewards of social behavior for up to two weeks from the time they were given MDMA. During this time, Dölen and her colleagues also found that the brains of the mice had corresponding responses to oxytocin, known as the "love hormone," which is made in the hypothalamus and acts in the brain as a signal between neurons that encode information about social rewards. They found these responses by looking more closely at synapses, the spaces between brain cells called neurons. Their experiments showed that, in mature mice given MDMA, oxytocin triggers signaling in the synapses that encodes learning and memory, which does not typically happen in mature mice.

Dölen says that opening the critical window for social reward behavior may also have implications for treating psychiatric conditions. A strong bond between a psychotherapist and patient is well-known to be important for successful treatment. If MDMA reopens the critical period for social reward learning in humans in the same way it does for mice, then it could explain why the drug has been successful in treating people with PTSD, perhaps by strengthening the psychotherapist-patient bond.

MDMA has been designated by the U.S. Food and Drug Administration as a "breakthrough therapy" for PTSD, meaning that the agency will fast-track the development and review of clinical trials to test it. However, the researchers caution that MDMA may not work for every psychiatric condition linked to social behaviors.

"As we develop new therapies or determine when to give these therapies, it's critical to know the biological mechanism on which they act," says Dölen.

Funding for the study was provided by the Kinship Foundation, Hartwell Foundation, Klingenstein-Simons Foundation, the National Institutes of Health (MH115177, 1R01NS075421), the New York Stem Cell Foundation-Robertson Award and the National Institutes of Health Director's Pioneer Award (1DP1NS087724).

In addition to Dölen and Nardou, other contributors to the study include Eastman M. Lewis and Rebecca Rothhaas from Johns Hopkins and Ran Xu, Aimei Yang and Edward Boyden from MIT.

https://www.sciencedaily.com/releases/2019/04/190404094832.htm

Study reveals how ecstasy acts on brain, hints at therapeutic uses

January 17, 2014

Science Daily/Imperial College London

Brain imaging experiments have revealed for the first time how ecstasy produces feelings of euphoria in users.

Results of the study at Imperial College London, parts of which were televised in Drugs Live on Channel 4 in 2012, have now been published in the journal Biological Psychiatry.

The findings hint at ways that ecstasy, or MDMA, might be useful in the treatment of anxiety and post-traumatic stress disorder (PTSD).

MDMA has been a popular recreational drug since the 1980s, but there has been little research on which areas of the brain it affects. The new study is the first to use functional magnetic resonance imaging (fMRI) on resting subjects under its influence.

Twenty-five volunteers underwent brain scans on two occasions, one after taking the drug and one after taking a placebo, without knowing which they had been given.

The results show that MDMA decreases activity in the limbic system -- a set of structures involved in emotional responses. These effects were stronger in subjects who reported stronger subjective experiences, suggesting that they are related.

Communication between the medial temporal lobe and medial prefrontal cortex, which is involved in emotional control, was reduced. This effect, and the drop in activity in the limbic system, are opposite to patterns seen in patients who suffer from anxiety.

MDMA also increased communication between the amygdala and the hippocampus. Studies on patients with PTSD have found a reduction in communication between these areas.

The project was led by David Nutt, the Edmond J. Safra Professor of Neuropsychopharmacology at Imperial College London, and Professor Val Curran at UCL.

Dr Robin Carhart-Harris from the Department of Medicine at Imperial, who performed the research, said: "We found that MDMA caused reduced blood flow in regions of the brain linked to emotion and memory. These effects may be related to the feelings of euphoria that people experience on the drug."

Professor Nutt added: "The findings suggest possible clinical uses of MDMA in treating anxiety and PTSD, but we need to be careful about drawing too many conclusions from a study in healthy volunteers. We would have to do studies in patients to see if we find the same effects."

MDMA has been investigated as an adjunct to psychotherapy in the treatment of PTSD, with a recent pilot study in the US reporting positive preliminary results.

As part of the Imperial study, the volunteers were asked to recall their favourite and worst memories while inside the scanner. They rated their favourite memories as more vivid, emotionally intense and positive after MDMA than placebo, and they rated their worst memories less negatively. This was reflected in the way that parts of the brain were activated more or less strongly under MDMA. These results were published in the International Journal of Neuropsychopharmacology.

Dr Carhart-Harris said: "In healthy volunteers, MDMA seems to lessen the impact of painful memories. This fits with the idea that it could help patients with PTSD revisit their traumatic experiences in psychotherapy without being overwhelmed by negative emotions, but we need to do studies in PTSD patients to see if the drug affects them in the same way."

https://www.sciencedaily.com/releases/2014/01/140117103941.htm

MDMA (Ecstasy)-assisted psychotherapy relieves treatment-resistant PTSD

July 20, 2010

Science Daily/SAGE Publications UK

MDMA (±3,4-methylenedioxymethamphetamine, also known as Ecstasy), may one day offer hope for individuals with posttraumatic stress disorder (PTSD), even people for whom other treatments have failed. Clinical trial results out July 19 in the Journal of Psychopharmacology suggests that MDMA can be administered to subjects with PTSD without evidence of harm and could offer sufferers a vital window with reduced fear responses where psychotherapy can take effect.

Before MDMA became used recreationally under the street name Ecstasy, hundreds of psychiatrists and psychotherapists around the world administered MDMA as a catalyst to psychotherapy. MDMA was criminalized in the US in 1985 (it had been illegal in the UK since 1977). Several decades later, this study is the first completed randomised, double-blinded clinical trial to evaluate MDMA as a therapeutic adjunct in any patient population.

Belmont, MA-based Rick Doblin, Ph.D., President of the Multidisciplinary Association for Psychedelic Studies (a non-profit psychedelic and medical marijuana research and educational organization that sponsored the study), together with South Carolina-based psychiatrist Michael Mithoefer, MD and colleagues, conducted a pilot Phase II clinical trial with 20 patients with chronic PTSD persisting for an average of over 19 years. Prior to enrolling in the MDMA study, subjects were required to have received, and failed to obtain relief, from both psychotherapy and psychopharmacology.

Participants treated with a combination of MDMA and psychotherapy saw clinically and statistically significant improvements in their PTSD -- over 80% of the trial group no longer met the diagnostic criteria for PTSD, stipulated in the Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV-TR) following the trial, compared to only 25% of the placebo group. In addition, all three subjects who reported being unable to work due to PTSD were able to return to work following treatment with MDMA.

The trial centred on two eight-hour psychotherapy sessions scheduled about 3-5 weeks apart, where 12 subjects received MDMA, and eight took a placebo. Subjects were also given psychotherapy on a weekly basis before and after each experimental session. A blinded, independent rater tested each subject using a PTSD scale at baseline, and at intervals four days after each session and two months after the second session. The clinical response was significant -- 10 of the 12 in the treatment group responded to the treatment compared with just two of the eight in the placebo group. During the trial, the subjects did not experience any drug-related Serious Adverse Events (SAEs), nor any adverse neurocognitive effects or clinically significant blood pressure or temperature increases.

After the two-month follow-up, subjects in the placebo group were offered the option to participate in the treatment process again, to receive MDMA on an open-label basis, acting as their own controls. Seven of the eight placebo subjects elected to receive MDMA-assisted psychotherapy, with successful treatment outcomes similar to the subjects initially randomized to MDMA.

PTSD involves exaggerated and uncontrolled fear responses. To treat these, psychotherapists need to help sufferers revisit traumatic experiences. But patients often suffer intolerable feelings when they revisit the trauma, or numb themselves emotionally, resulting in the psychotherapy having little effect. The goal of using MDMA is to temporarily reduce fear and increase trust without inhibiting emotions, especially painful emotions, allowing these patients a window where psychotherapy for their PTSD is effective.

MDMA's pharmacological effects include serotonin release, 5HT2 receptor stimulation and increase in levels of the neurohormones oxytocin, prolactin and cortisol.

Importantly, this trial involved concentrated periods of patient-therapist contact (31 hours over two months) including two all-day therapy sessions and overnight stays in the clinic. "These are not usual features of psychotherapy practice in the outpatient setting," says Michael Mithoefer. MDMA-assisted psychotherapy would require special clinics equipped for longer treatment sessions and overnight stays if an MDMA-based treatment were approved. "This method also involves patient preparation and close follow-up to support further processing of emotions and integration of cognitive shifts that may occur," Mithoefer adds, stressing that these are vital for safety and therapeutic effect.

Measures like these may prove a price worth paying, however, to alleviate the debilitating effects of PTSD on sufferers in future.

The authors caution that the study does have limitations -- for example they did not look at gender and ethnic factors in their sample selection. Another important limitation was that most participants and trial investigators guessed accurately whether they were in the treatment or the placebo group. The placebo had no psychoactive effect and investigators could detect raised blood pressure and other symptoms in the MDMA group. A long-term follow-up to the study just published, evaluating subjects an average of about 40 months post-treatment, is underway.

The investigators have now received the go ahead from the US Food and Drug Administration (FDA) for a protocol for a three-arm, dose-response design that they expect will result in successful blinding. This new study is for US veterans with war-related PTSD, most from Iraq and Afghanistan and a few from Vietnam. MAPS is currently sponsoring MDMA/PTSD Phase 2 pilot studies in Switzerland and Israel, and is working to start additional pilot studies in Canada, Jordan and Spain.

https://www.sciencedaily.com/releases/2010/07/100719082927.htm